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alpha-synuclein

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Description

alpha-Synuclein: A synuclein that is a major component of LEWY BODIES and plays a role in SYNUCLEINOPATHIES, neurodegeneration and neuroprotection. [Medical Subject Headings (MeSH), National Library of Medicine, extracted Dec-2023]

Cross-References

ID SourceID
PubMed CID10307709
MeSH IDM0159750

Synonyms (5)

Synonym
alpha-synuclein
EX-A7463
440645-08-9
AKOS040758135
??-synuclein (61-75)

Research Excerpts

Toxicity

Alpha-synuclein (αS) fibrils are toxic to cells and contribute to the pathogenesis and progression of Parkinson's disease and other synucleinopathies. DJ-1 protects dopaminergic neurons from oxidative stress through up-regulation of glutathione synthesis.

ExcerptReferenceRelevance
" These results suggest that an intermediate, which exhibits beta-sheet structure, may be responsible for the toxic properties of NAC and provides further evidence for the role of NAC in the pathogenesis of AD, PD and DLB."( Toxicity of non-abeta component of Alzheimer's disease amyloid, and N-terminal fragments thereof, correlates to formation of beta-sheet structure and fibrils.
Bodles, AM; Campbell, P; Guthrie, DJ; Harriott, P; Irvine, GB, 2000
)
0.31
" In contrast, alpha-synuclein is not toxic in non-dopaminergic human cortical neurons, but rather exhibits neuroprotective activity."( Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease.
Jin, LW; Kao, SY; Lee, FJ; Song, W; Xu, J; Yankner, BA, 2002
)
0.95
" Parkin is capable of rescuing the toxic effects of mutant alpha-synuclein or proteasome inhibition in these cells."( Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons.
Baptista, M; Choi, P; Cookson, MR; Farrer, M; Hardy, J; Kehoe, K; Lockhart, PJ; O'Farrell, C; Petrucelli, L; Vink, L; Wolozin, B, 2002
)
0.8
" We therefore favor a toxic protofibril scenario, and propose that the pathogenic species is transiently populated during the process of fibrillization."( Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson's disease.
Lansbury, PT; Volles, MJ, 2003
)
0.59
" Whereas alpha-synuclein(68-78) formed fibrils and was toxic to cells, the N-methylated analogue had neither of these properties."( Inhibition of fibril formation and toxicity of a fragment of alpha-synuclein by an N-methylated peptide analogue.
Bodles, AM; El-Agnaf, OM; Greer, B; Guthrie, DJ; Irvine, GB, 2004
)
0.98
" We propose that both synucleins are important for effective survival of SNpc neurones during critical period of development but, in the absence of these proteins, permanent activation of compensatory mechanisms allow many neurones to survive and become resistant to certain toxic insults."( Developmental loss and resistance to MPTP toxicity of dopaminergic neurones in substantia nigra pars compacta of gamma-synuclein, alpha-synuclein and double alpha/gamma-synuclein null mutant mice.
Buchman, VL; Jones, PA; Ninkina, N; Robertson, DC; Schmidt, O; Sharkey, J, 2004
)
0.53
" Our data indicate that DJ-1 protects dopaminergic neurons from oxidative stress through up-regulation of glutathione synthesis and from the toxic consequences of mutant humanalpha-synuclein through increased expression of heat shock protein 70."( DJ-1 up-regulates glutathione synthesis during oxidative stress and inhibits A53T alpha-synuclein toxicity.
Freed, CR; Zhou, W, 2005
)
0.75
" Mutant (A30P and A53T) alpha-synuclein isoforms cause increased vulnerability of cells towards various toxic insults and enhance dopamine transporter (DAT)-mediated toxicity of the selective dopaminergic neurotoxin and mitochondrial complex I inhibitor MPP(+) in vitro."( Dopamine transporter-mediated cytotoxicity of 6-hydroxydopamine in vitro depends on expression of mutant alpha-synucleins related to Parkinson's disease.
Lehmensiek, V; Lenk, T; Liebau, S; Schwarz, J; Storch, A; Tan, EM; Zettlmeisl, H, 2006
)
0.85
" Surprisingly, alpha-synuclein was not toxic to several yeast strains tested."( alpha-Synuclein budding yeast model: toxicity enhanced by impaired proteasome and oxidative stress.
Brandis, KA; Debburman, SK; Herrera, SK; Johnson, BE; Sharma, N; Shrestha, R; Vaidya, T, 2006
)
2.13
" Aggregated forms of the protein, especially newly formed soluble aggregates, are toxic to cells, so that one therapeutic strategy would be to reduce the rate at which such oligomerization occurs."( Inhibitors of alpha-synuclein oligomerization and toxicity: a future therapeutic strategy for Parkinson's disease and related disorders.
Amer, DA; El-Agnaf, OM; Irvine, GB, 2006
)
0.69
" A mutant designed by molecular modelling to be amphipathic was shown to be significantly less fusogenic and toxic than the wild type."( Tilted properties of the 67-78 fragment of alpha-synuclein are responsible for membrane destabilization and neurotoxicity.
Brasseur, R; Charloteaux, B; Crowet, JM; Dupiereux, I; Elmoualija, B; Heinen, E; Lins, L; Lorin, A; Stroobant, V, 2007
)
0.6
"5mg/kg PM treatments antagonized the toxic effect of MPTP on TH and DAT expression (p<0."( Neurotoxicity in murine striatal dopaminergic pathways following long-term application of low doses of permethrin and MPTP.
Bloomquist, JR; Kou, J, 2007
)
0.34
"alpha-Synuclein is one of the principal toxic triggers of Parkinson disease, an age-associated neurodegeneration."( Functional mitochondria are required for alpha-synuclein toxicity in aging yeast.
Augsten, M; Bitto, A; Büttner, S; Carmona-Gutierrez, D; Eisenberg, T; Hutter, S; Jungwirth, H; Kroemer, G; Madeo, F; Ring, J; Winderickx, J; Zabrocki, P, 2008
)
2.05
" It was found that the inhibition of neuronal and inducible nitric oxide synthase reversed the toxic effect of alpha-synuclein in control but not in APPsw cells."( alpha-Synuclein enhances secretion and toxicity of amyloid beta peptides in PC12 cells.
Adamczyk, A; Kazmierczak, A; Strosznajder, JB, 2008
)
2
" Other members of the synuclein family showed no toxicity in any form and inherited point mutations did not alter the effective toxic concentration of alpha-synuclein."( Unique copper-induced oligomers mediate alpha-synuclein toxicity.
Brown, DR; Wang, X; Wright, JA, 2009
)
0.82
"Intracellular clearance of toxic protein aggregates represents a promising therapeutic approach to treat protein-misfolding diseases such as Parkinson's and Huntington's diseases."( Intracellular targeting and clearance of oligomeric alpha-synuclein alleviates toxicity in mammalian cells.
Sierks, MR; Yuan, B, 2009
)
0.6
" Efforts to purify the toxic activity revealed that it is a highly stable, lipophilic, and chemically unique small molecule."( Investigating bacterial sources of toxicity as an environmental contributor to dopaminergic neurodegeneration.
Armagost, J; Blalock, JE; Caldwell, GA; Caldwell, KA; Chen, J; DeLeon, SM; Findlay, RH; Hodges, TW; Memon, SB; Olson, JB; Ruan, Q; Standaert, DG; Tucci, ML; Webber, PJ, 2009
)
0.35
" Similarly, the misfolding of the beta-cell hormone human islet amyloid polypeptide (h-IAPP) into toxic oligomers plays a central role in the induction of beta-cell apoptosis in the context of type 2 diabetes."( Annexin A5 directly interacts with amyloidogenic proteins and reduces their toxicity.
Bedrood, S; Butler, PC; Chen, M; Erbel, S; Jayasinghe, S; Langen, R; Ritzel, RA; Sieburth, D, 2009
)
0.35
" Our findings suggest that alpha-synuclein neurotoxicity in Parkinson disease and related synucleinopathies may result from an imbalance between the detrimental, oligomer-promoting effect of serine 129 phosphorylation and a neuroprotective action of tyrosine 125 phosphorylation that inhibits toxic oligomer formation."( Tyrosine and serine phosphorylation of alpha-synuclein have opposing effects on neurotoxicity and soluble oligomer formation.
Chen, L; Feany, MB; Hyman, BT; McLean, PJ; Negro, A; Periquet, M; Wang, X, 2009
)
0.92
" We also show that both intracellular overexpression of alphaS and extracellular addition of oligomeric alphaS increase ROS which induces apoptosis, suggesting that aggregated alphaS may induce similar toxic effects whether it is generated intra- or extracellulary."( Curcumin reduces alpha-synuclein induced cytotoxicity in Parkinson's disease cell model.
Boddapati, S; Emadi, S; Sierks, MR; Wang, MS, 2010
)
0.7
" Elucidating the molecular mechanisms underlying post-translation modifications of alpha-syn and the consequences of such modifications on the biochemical, structural, aggregation and toxic properties of the protein is essential for unravelling the molecular basis of its function(s) in health and disease."( Role of post-translational modifications in modulating the structure, function and toxicity of alpha-synuclein: implications for Parkinson's disease pathogenesis and therapies.
Fournier, M; Lashuel, HA; Oueslati, A, 2010
)
0.58
" Amyloid fibrils formed from IAPP, intermediates generated in the assembly of IAPP amyloid, or both are toxic to β-cells, suggesting that islet amyloid formation may contribute to the pathology of type 2 diabetes."( The flavanol (-)-epigallocatechin 3-gallate inhibits amyloid formation by islet amyloid polypeptide, disaggregates amyloid fibrils, and protects cultured cells against IAPP-induced toxicity.
Abedini, A; Meng, F; Plesner, A; Raleigh, DP; Verchere, CB, 2010
)
0.36
" Our findings indicate that NAC peptide exerts its toxic effect by activation of p53/Cdk5 and Bax-dependent apoptotic signaling pathway."( A novel mechanism of non-Aβ component of Alzheimer's disease amyloid (NAC) neurotoxicity. Interplay between p53 protein and cyclin-dependent kinase 5 (Cdk5).
Adamczyk, A; Czapski, GA; Gajkowska, B; Kaźmierczak, A; Strosznajder, JB, 2011
)
0.37
" Inhibitors of ceramide synthesis, myriocin and FB1, were extremely toxic to wild-type yeast cells expressing (WT, A53T, or E46K) α-syn but much less toxic to cells expressing A30P."( Defects in very long chain fatty acid synthesis enhance alpha-synuclein toxicity in a yeast model of Parkinson's disease.
Lee, YJ; Slone, SR; Wang, S; Witt, SN; Yacoubian, TA, 2011
)
0.62
" These observations suggest that high levels of shRNA-SNCA were toxic to DA neurons, while neighboring neurons exposed to lower levels were protected by hSNCA gene silencing."( An α-synuclein AAV gene silencing vector ameliorates a behavioral deficit in a rat model of Parkinson's disease, but displays toxicity in dopamine neurons.
Bankiewicz, KS; Bohn, MC; Han, Y; Kells, AP; Khodr, CE; Pedapati, J; Sapru, MK; West, NC, 2011
)
0.37
" We show that both Synphilin-1 and α-synuclein are toxic by themselves, but when co-expressed, they suppress their toxicity reciprocally."( Synphilin suppresses α-synuclein neurotoxicity in a Parkinson's disease Drosophila model.
Fonseca-Ornelas, L; Hernández-Vargas, R; López-González, I; Reynaud, E; Riesgo-Escovar, J; Zurita, M, 2011
)
0.37
" Noopept does not bind to a sterically specific site in the α-Syn molecule as revealed by heteronuclear two-dimensional NMR analysis, but due to hydrophobic interactions with toxic amyloid oligomers, it prompts their rapid sequestration into larger fibrillar amyloid aggregates."( Neuroprotective and nootropic drug noopept rescues α-synuclein amyloid cytotoxicity.
Gharibyan, AL; Jia, X; Liu, Y; Morozova-Roche, LA; Öhman, A; Olofsson, A, 2011
)
0.37
" These data suggest a mechanism of action for Mel, inhibition of assembly of toxic polymers and protection of neurons from their effect."( Effect of melatonin on α-synuclein self-assembly and cytotoxicity.
Ikeda, T; Mochizuki, H; Nihira, T; Ono, K; Takasaki, J; Teplow, DB; Yamada, M, 2012
)
0.38
" Strikingly, overexpression of the phosphomimic mutant S87E did not show any toxic effect on dopaminergic neurons and resulted in significantly less α-syn aggregates, dystrophic fibers, and motor impairment."( Mimicking phosphorylation at serine 87 inhibits the aggregation of human α-synuclein and protects against its toxicity in a rat model of Parkinson's disease.
Aebischer, P; Lashuel, HA; Oueslati, A; Paleologou, KE; Schneider, BL, 2012
)
0.38
" Recent studies in yeast have shown that, at toxic levels, αSyn disrupts Rab homeostasis, causing an initial endoplasmic reticulum-to-Golgi block that precedes a generalized trafficking collapse."( Suppression of α-synuclein toxicity and vesicle trafficking defects by phosphorylation at S129 in yeast depends on genetic context.
Griffith, J; Lee, SA; Masliah, E; Muchowski, PJ; Outeiro, TF; Patrick, C; Paulino, A; Reggiori, F; Sancenon, V, 2012
)
0.38
" Compared to the unmodified monomer, the photoinduced covalent oligomeric species demonstrated increased toxic effects on differentiated neuronal-like SH-SY5Y cells."( Biophysical properties and cellular toxicity of covalent crosslinked oligomers of α-synuclein formed by photoinduced side-chain tyrosyl radicals.
Borsarelli, CD; Falomir-Lockhart, LJ; Fauerbach, JA; Hsiao, HH; Jares-Erijman, EA; Jovin, TM; Ostatná, V; Paleček, E; Urlaub, H, 2012
)
0.38
" The protein α-synuclein (αSyn), the principle toxic effector in PD, has been shown to interfere with neuronal Ca(2+) fluxes, arguing for an involvement of deregulated Ca(2+) homeostasis in this neuronal demise."( The Ca2+/Mn2+ ion-pump PMR1 links elevation of cytosolic Ca(2+) levels to α-synuclein toxicity in Parkinson's disease models.
Benke, S; Broeskamp, F; Büttner, S; Callewaert, G; Carmona-Gutierrez, D; D'hooge, P; Eisenberg, T; Faes, L; Franssens, V; Freudenberger, P; Ghillebert, R; Habernig, L; Harger, A; Kourtis, N; Kroemer, G; Madeo, F; Pieber, TR; Reichelt, WN; Ruli, D; Sigrist, SJ; Tavernarakis, N; Winderickx, J, 2013
)
0.39
" However, a detailed mechanism of α-Syn aggregation/fibrillogenesis and the exact nature of toxic oligomeric species produced during amyloid formation process are still unknown."( Aggregation and neurotoxicity of recombinant α-synuclein aggregates initiated by dimerization.
Beaudoin, S; Roostaee, A; Roucou, X; Staskevicius, A, 2013
)
0.39
" These recombinant toxic aggregates further converted into non-toxic amyloids which were successfully amplified by protein misfolding cyclic amplification method, providing the first evidence for the in vitro propagation of synthetic α-Syn aggregates."( Aggregation and neurotoxicity of recombinant α-synuclein aggregates initiated by dimerization.
Beaudoin, S; Roostaee, A; Roucou, X; Staskevicius, A, 2013
)
0.39
" The acceleration of aggregation by curcumin may decrease the population of toxic oligomeric intermediates of α-Syn."( Curcumin modulates α-synuclein aggregation and toxicity.
Ghosh, D; Kotia, V; Kumar, A; Maji, SK; Mohite, GM; Singh, PK, 2013
)
0.39
" We have previously demonstrated that naturally secreted AS species, derived from SH-SY5Y cells inducibly overexpressing human wild type AS, can be toxic to recipient neuronal cells."( Deregulation of calcium homeostasis mediates secreted α-synuclein-induced neurotoxicity.
Emmanouilidou, E; Masgrau, R; Melachroinou, K; Papazafiri, P; Stefanis, L; Vekrellis, K; Xilouri, M, 2013
)
0.39
" Recent studies have shown that the nuclear accumulation of α-syn might have a toxic effect."( The nuclear accumulation of alpha-synuclein is mediated by importin alpha and promotes neurotoxicity by accelerating the cell cycle.
Chen, NH; Gao, K; Han, N; Ma, KL; Song, LK; Yuan, YH; Zhang, Y, 2014
)
0.7
" Aggregates of aS, which form a transient, complex and heterogeneous ensemble, participate in a wide variety of toxic mechanisms that may be amplified by aS spreading among neighbouring neurons."( Biophysical groundwork as a hinge to unravel the biology of α-synuclein aggregation and toxicity.
Bisaglia, M; Bubacco, L; Greggio, E; Plotegher, N, 2014
)
0.4
" To compare the mechanism by which the splice isoforms exert toxicity, equally toxic strains were probed with genetic modifiers of α-syn-induced toxicity."( Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity.
Lindquist, S; Termine, DJ; Valastyan, JS, 2014
)
0.4
" In animal models of these diseases, axon pathology often precedes cell death, raising the question of whether aSyn has compartment-specific toxic effects that could require early and/or independent therapeutic intervention."( Axon degeneration and PGC-1α-mediated protection in a zebrafish model of α-synuclein toxicity.
Bronstein, JM; Lulla, A; O'Donnell, KC; Sagasti, A; Stahl, MC; Wheat, ND, 2014
)
0.4
" Here, we demonstrate that the toxic effect exerted by α-synuclein oligomers in dopaminergic cell culture is abolished in the presence of GAPDH prefibrillar species."( Structural characterization of heparin-induced glyceraldehyde-3-phosphate dehydrogenase protofibrils preventing α-synuclein oligomeric species toxicity.
Ávila, CL; Barbosa, LR; Celej, MS; Chehín, RN; Itri, R; Ouidja, MO; Papy-Garcia, D; Raisman-Vozari, R; Sales, EM; Socías, SB; Torres-Bugeau, CM, 2014
)
0.4
" Treatment with pharmacological mGluR5 inhibitors such as 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) attenuated the toxic effects of Aβ in α-syn-expressing neuronal cells."( Hippocampal neuronal cells that accumulate α-synuclein fragments are more vulnerable to Aβ oligomer toxicity via mGluR5--implications for dementia with Lewy bodies.
Cartier, A; Desplats, P; Masliah, E; Overk, CR; Patrick, C; Price, DL; Rockenstein, E; Shaked, G; Spencer, B; Ubhi, K, 2014
)
0.4
"It is widely recognized that bacterial metabolites have toxic effects in animal systems."( Phenazine derivatives cause proteotoxicity and stress in C. elegans.
Caldwell, GA; Caldwell, KA; Ray, A; Rentas, C, 2015
)
0.42
" Toxic α-synuclein oligomers may impact cells in a number of ways, including the disruption of membranes, mitochondrial depolarization, cytoskeleton changes, impairment of protein clearance pathways, and enhanced oxidative stress."( Seeking a mechanism for the toxicity of oligomeric α-synuclein.
Brown, DR; Roberts, HL, 2015
)
0.42
"Aggregation and aggregation-mediated formation of toxic alpha synuclein (aSyn) species have been linked to the pathogenesis of sporadic and monogenic Parkinson's disease (PD)."( Posttranslational modification and mutation of histidine 50 trigger alpha synuclein aggregation and toxicity.
Becker, CM; Hoffmann, AC; Klucken, J; Meixner, H; Menges, S; Schlachetzki, JC; Schlötzer-Schrehardt, U; Winkler, J; Xiang, W, 2015
)
0.42
"Accumulating evidence suggests that deposition of neurotoxic α-synuclein aggregates in the brain during the development of neurodegenerative diseases like Parkinson's disease can be curbed by anti-aggregation strategies that either disrupt or eliminate toxic aggregates."( Curcumin Pyrazole and its derivative (N-(3-Nitrophenylpyrazole) Curcumin inhibit aggregation, disrupt fibrils and modulate toxicity of Wild type and Mutant α-Synuclein.
Ahsan, N; Gupta, S; Jain, MK; Mishra, S; Surolia, A, 2015
)
0.42
" Far-UV CD spectroscopy and fluorescence quenching analysis revealed that caffeine induced transient changes in this intrinsically disordered protein, forming a non-native species that enhanced the rate of aggregation of α-synuclein and modified the population of mature aggregates, introducing a higher fraction of amorphous, less toxic species."( Understanding Caffeine's Role in Attenuating the Toxicity of α-Synuclein Aggregates: Implications for Risk of Parkinson's Disease.
Kardani, J; Roy, I, 2015
)
0.42
" However, there is still no consensus with respect to the toxic forms of alpha-synuclein, hampering our ability to use the protein as a target for therapeutic intervention."( Structure, function and toxicity of alpha-synuclein: the Bermuda triangle in synucleinopathies.
Lopes da Fonseca, T; Outeiro, TF; Villar-Piqué, A, 2016
)
0.94
" Cell culture and animal model studies suggest that misfolded, aggregated α-synuclein is actively translocated via the cytoskeletal system to a region of the cell where other factors that help to lessen the toxic effects can also be recruited."( Direct and/or Indirect Roles for SUMO in Modulating Alpha-Synuclein Toxicity.
Antony, H; Pountney, DL; Vijayakumaran, S; Wong, MB, 2015
)
0.67
" Aggregation of α-SYN leads to toxic species involved in the degeneration of dopaminergic neurons in the midbrain."( Alpha-Synuclein Fibrils Interact with Dopamine Reducing its Cytotoxicity on PC12 Cells.
Aliakbari, F; Azimzadeh Jamalkandi, S; Khalife, M; Mohammad Beigi, H; Morshedi, D; Pan-Montojo, F; Tayaranian Marvian, A, 2015
)
1.86
" In addition, cytotoxicity assays on PC12 cells showed that cuminaldehyde is a nontoxic compound, treatment with cuminaldehyde throughout α-SN fibrillation showed no toxic effects on the cells."( Cuminaldehyde as the Major Component of Cuminum cyminum, a Natural Aldehyde with Inhibitory Effect on Alpha-Synuclein Fibrillation and Cytotoxicity.
Aliakbari, F; Fassihi, A; Morshedi, D; Pan-Montojo, F; Pérez-Sánchez, H; Tayaranian-Marvian, A, 2015
)
0.63
" One of these proteins, α-synuclein, is a toxic aggregating protein associated with synucleinopathies, including Parkinson's disease."( O-GlcNAc modification blocks the aggregation and toxicity of the protein α-synuclein associated with Parkinson's disease.
Ambroso, MR; Arnold, DB; Langen, R; Lewis, YE; Lin, YH; Marotta, NP; Pratt, MR; Roth, MT; Zaro, BW, 2015
)
0.42
" We found that bSyn is toxic and forms cytosolic inclusions that are similar to those formed by aSyn."( Yeast reveals similar molecular mechanisms underlying alpha- and beta-synuclein toxicity.
Becker, S; Braus, GH; Favretto, F; Gerhardt, E; Magalhães, F; Outeiro, TF; Popova, B; Rosado-Ramos, R; Tenreiro, S; Zweckstetter, M, 2016
)
0.43
" The toxic oligomer hypothesis stipulates that prefibrillar assemblies, such as soluble oligomers or protofibrils, are responsible for the poor prognosis of these diseases."( Stabilization of α-Synuclein Fibril Clusters Prevents Fragmentation and Reduces Seeding Activity and Toxicity.
Bieschke, J; Gentry, KA; Graber, MC; Lam, HT, 2016
)
0.43
" Compounds that modulate α-Syn aggregation and interact with preformed fibrils/oligomers and convert them to less toxic species could have promising applications in the drug development efforts against PD."( Effect of curcumin analogs onα-synuclein aggregation and cytotoxicity.
Anoop, A; Ayyagari, N; Das, S; Ghosh, D; Jacob, RS; Jha, NN; Maji, SK; Namboothiri, IN; Singh, PK, 2016
)
0.43
" Here, we demonstrate how the self-assembled, cyclic d,l-α-peptide CP-2, which has similar structural and functional properties to those of amyloids, acts as a generic inhibitor of the Parkinson's disease associated α-synuclein (α-syn) aggregation to toxic oligomers by an "off-pathway" mechanism."( Self-Assembled Cyclic d,l-α-Peptides as Generic Conformational Inhibitors of the α-Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies.
Chemerovski-Glikman, M; Chill, JH; Cohen, HY; Getler, A; Gräslund, A; Grupi, A; Haas, E; Rahimipour, S; Richman, M; Rozentur-Shkop, E; Shaked, H; Wallin, C; Wärmländer, SK, 2016
)
0.43
"Several neurodegenerative diseases are driven by the toxic gain-of-function of specific proteins within the brain."( TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau.
Al-Ramahi, I; Botas, J; de Haro, M; De Maio, A; Jafar-Nejad, P; Klisch, TJ; Lasagna-Reeves, CA; Lu, N; Park, J; Rousseaux, MW; See, L; Sharma, A; Troncoso, JC; Vilanova-Velez, L; Westbrook, TF; Zoghbi, HY, 2016
)
0.67
"In Parkinson's disease, abnormal alpha-synuclein (asyn) accumulation leads to the formation of soluble oligomeric species thought to be toxic to cells as well as intraneuronal inclusions."( Toxic effects of human and rodent variants of alpha-synuclein in vivo.
Buck, K; Kirik, D; Landeck, N, 2017
)
0.99
" Furthermore, these samples reduce the toxic effects of CUR."( Curcumin-Loaded Amine-Functionalized Mesoporous Silica Nanoparticles Inhibit α-Synuclein Fibrillation and Reduce Its Cytotoxicity-Associated Effects.
Aliakbari, F; Arpanaei, A; Morshedi, D; Rahimi, F; Taebnia, N; Yaghmaei, S, 2016
)
0.43
" Accordingly, we hypothesized that protein binding partners of lipid-associated aSyn could inhibit the formation of toxic aSyn oligomers at membrane surfaces."( Endosulfine-alpha inhibits membrane-induced α-synuclein aggregation and protects against α-synuclein neurotoxicity.
Bezard, E; Costantino, IM; Dehay, B; Frosch, MP; George, JM; McCabe, GP; Rochet, JC; Ysselstein, D, 2017
)
0.46
" The alkaloid increases the lag time of the nucleation step and reduces the build-up of the more toxic oligomeric species in a concentration-dependent manner."( Nicotine slows down oligomerisation of α-synuclein and ameliorates cytotoxicity in a yeast model of Parkinson's disease.
Kardani, J; Roy, I; Sethi, R, 2017
)
0.46
" This enhanced vulnerability likely relates to the toxic effects of METH that overlap with PD pathology, for example, aberrant functioning of α-synuclein and parkin."( Self-administration of methamphetamine alters gut biomarkers of toxicity.
Celeste Napier, T; Flack, A; Kousik, SM; Moszczynska, A; Persons, AL, 2017
)
0.46
" Findings from in vitro aggregation and kinetics assays support the view that NOR inhibits aggregation of α-syn by directly binding to the soluble, monomeric form, and by enhancing reconfiguration of the monomer, inhibits formation of toxic conformations of the protein."( Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form.
Collier, TJ; de Oliveira, P; Dettmer, U; Feany, MB; Grammatopoulous, T; Havas, D; Hutter-Paier, B; Jock, K; Justman, C; Lansbury, P; Lapidus, L; Liu, F; Paumier, KL; Prokesch, M; Rochet, JC; Sortwell, CE; Srivastava, KR; Stirtz, GL, 2017
)
0.7
" To investigate aSyn toxic mechanisms, we have developed a primary neuronal model in which a longitudinal survival analysis can be performed by following the overexpression of fluorescently tagged WT or pathologically mutant aSyn constructs."( E46K α-synuclein pathological mutation causes cell-autonomous toxicity without altering protein turnover or aggregation.
Arrasate, M; Bugallo, R; Íñigo-Marco, I; Larrea, L; Martínez-Goikoetxea, M; Valencia, M; Zuriguel, I, 2017
)
0.46
" The association between copper and α-syn results in the formation of stellate toxic oligomers that are highly toxic to cultured neurons."( Levels of α- and β-synuclein regulate cellular susceptibility to toxicity from α-synuclein oligomers.
Angelova, DM; Brown, DR; Jones, HBL, 2018
)
0.48
" By using solution and solid-state nuclear magnetic resonance techniques in conjunction with other structural methods, we identified the fundamental characteristics that enable toxic α-synuclein oligomers to perturb biological membranes and disrupt cellular function; these include a highly lipophilic element that promotes strong membrane interactions and a structured region that inserts into lipid bilayers and disrupts their integrity."( Structural basis of membrane disruption and cellular toxicity by α-synuclein oligomers.
Cascella, R; Cecchi, C; Chen, SW; Chiti, F; Cremades, N; De Simone, A; Dobson, CM; Fusco, G; Jarvis, JA; Perni, M; Vendruscolo, M; Williamson, PTF; Ying, L, 2017
)
0.46
" By facilitating the fibril formation and thus eliminating the toxic AOs, EGCG was shown to suppress the membrane disrupting radiating amyloid fibril formation on the surface of liposomal membranes and thus protect the cells which could be readily affected by AOs."( EGCG-mediated Protection of the Membrane Disruption and Cytotoxicity Caused by the 'Active Oligomer' of α-Synuclein.
Bhak, G; Lee, JT; Lee, S; Paik, SR; Park, JH; Rhoo, KY; Yang, JE, 2017
)
0.46
" Our studies showed that osmotic toxicity had an adverse effect on α-synuclein aggregation, autophagic puncta, lipid content and oxidative stress."( Osmotic stress induced toxicity exacerbates Parkinson's associated effects via dysregulation of autophagy in transgenic C. elegans model.
Jadiya, P; Mir, SS; Nazir, A, 2018
)
0.48
" However, evidence shows that smaller, oligomeric aggregates are likely the most toxic form of the protein."( Tau oligomers mediate α-synuclein toxicity and can be targeted by immunotherapy.
Barrett, A; Carretero Murillo, M; Castillo-Carranza, DL; Farmer, KM; Gerson, JE; Henson, N; Kayed, R; Sengupta, U, 2018
)
0.48
" Levels of toxic tau oligomers were specifically decreased in the brains of TOMA-treated mice."( Tau oligomers mediate α-synuclein toxicity and can be targeted by immunotherapy.
Barrett, A; Carretero Murillo, M; Castillo-Carranza, DL; Farmer, KM; Gerson, JE; Henson, N; Kayed, R; Sengupta, U, 2018
)
0.48
"Amyloid assemblies of certain proteins, including the Parkinson disease-related protein α-synuclein, are commonly associated with the development and spreading of neurodegenerative diseases, although the nature of the most toxic forms and the mechanisms by which they trigger neurodegeneration remain largely unknown."( Preparation of α-Synuclein Amyloid Assemblies for Toxicity Experiments.
Chen, SW; Cremades, N, 2018
)
0.48
"Safety and tolerability assessments included physical and neurological examinations, laboratory tests, vital signs, and adverse events."( Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial.
Boess, FG; Ellenbogen, A; Goodman, I; Griffith, SG; Grundman, M; Isaacson, SH; Jankovic, J; Kinney, GG; Koller, M; Marmon, TK; Martin-Facklam, M; Ness, DK; Omidvar, O; Ostrowitzki, S; Quinn, JF; Safirstein, B; Schenk, DB; Soto, J; Zago, W, 2018
)
0.48
" PRX002 was generally safe and well tolerated; no serious or severe PRX002-related treatment-emergent adverse events (TEAEs) were reported."( Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial.
Boess, FG; Ellenbogen, A; Goodman, I; Griffith, SG; Grundman, M; Isaacson, SH; Jankovic, J; Kinney, GG; Koller, M; Marmon, TK; Martin-Facklam, M; Ness, DK; Omidvar, O; Ostrowitzki, S; Quinn, JF; Safirstein, B; Schenk, DB; Soto, J; Zago, W, 2018
)
0.48
"Single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral α-synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated α-synuclein in the brain."( Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial.
Boess, FG; Ellenbogen, A; Goodman, I; Griffith, SG; Grundman, M; Isaacson, SH; Jankovic, J; Kinney, GG; Koller, M; Marmon, TK; Martin-Facklam, M; Ness, DK; Omidvar, O; Ostrowitzki, S; Quinn, JF; Safirstein, B; Schenk, DB; Soto, J; Zago, W, 2018
)
0.48
" Adverse events were systematically recorded."( Feasibility and Safety of Multicenter Tissue and Biofluid Sampling for α-Synuclein in Parkinson's Disease: The Systemic Synuclein Sampling Study (S4).
Adler, CH; Arnedo, V; Beach, TG; Brumm, M; Caspell-Garcia, C; Chahine, LM; Coffey, CS; Dave, KD; Ecklund, D; Foroud, T; Jennings, D; Linder, C; Mollenhauer, B; Mosovsky, S; Riley, L; Riss, H; Seedorff, N; Seibyl, J; Serrano, GE, 2018
)
0.48
" Mild adverse events were common, especially for submandibular gland biopsy, but only 1 severe adverse event occurred."( Feasibility and Safety of Multicenter Tissue and Biofluid Sampling for α-Synuclein in Parkinson's Disease: The Systemic Synuclein Sampling Study (S4).
Adler, CH; Arnedo, V; Beach, TG; Brumm, M; Caspell-Garcia, C; Chahine, LM; Coffey, CS; Dave, KD; Ecklund, D; Foroud, T; Jennings, D; Linder, C; Mollenhauer, B; Mosovsky, S; Riley, L; Riss, H; Seedorff, N; Seibyl, J; Serrano, GE, 2018
)
0.48
"The mechanism underlying the role of Hsp70s in toxicity associated with intracellular accumulation of toxic protein inclusions is under intense investigation."( The yeast stress inducible Ssa Hsp70 reduces α-synuclein toxicity by promoting its degradation through autophagy.
Gupta, A; Pandey, R; Puri, A; Sharma, D; Singh, P; Sonam, S, 2018
)
0.48
" These results add insight into the mechanisms by which pα-syn* exerts its toxic effects that include the phosphorylation of several kinases of the MAPK pathway, as well as the formation of ptau at the mitochondrial membrane, likely contributing to mitotoxicity."( Pα-syn* mitotoxicity is linked to MAPK activation and involves tau phosphorylation and aggregation at the mitochondria.
Diaz-Perez, N; Grassi, D; Lasmézas, CI; Volpicelli-Daley, LA, 2019
)
0.51
" Deterioration of UPS and autophagy activities with aging further aggravates this toxic cycle."( Caloric restriction rescues yeast cells from alpha-synuclein toxicity through autophagic control of proteostasis.
Ludovico, P; Pereira, H; Sampaio-Marques, B; Santos, AR; Teixeira, A, 2018
)
0.74
" Besides, aegeline also prevented growth block in cells expressing the more toxic A53T α-synuclein mutant."( Aegeline, a natural product from the plant Aegle marmelos, mimics the yeast SNARE protein Sec22p in suppressing α-synuclein and Bax toxicity in yeast.
Bharate, SB; Chaudhuri, B; Derf, A; Sharma, A, 2019
)
0.51
" A prime example is α-synuclein, which forms toxic aggregates that are associated with neurodegeneration in Parkinson's and related diseases."( α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson's disease.
Balana, AT; De Leon, CA; Galesic, A; Lashuel, HA; Levine, PM; Mahul-Mellier, AL; Navarro, MX; Pratt, MR, 2019
)
0.51
" In contrast, it suggests the stabilization of native, compact ensembles as a potential therapeutic strategy to avoid the formation of toxic species and to target the early stages of PD."( Biasing the native α-synuclein conformational ensemble towards compact states abolishes aggregation and neurotoxicity.
Brás, IC; Carija, A; Grandori, R; Lázaro, DF; Navarro, S; Outeiro, TF; Pinheiro, F; Pujols, J; Santambrogio, C; Ventura, S, 2019
)
0.51
" Genetic screens in yeast provided important insight into the toxic mechanisms associated with the accumulation of misfolded proteins."( Yeast-Based Screens to Target Alpha-Synuclein Toxicity.
Brás, IC; Braus, GH; Outeiro, TF; Popova, B, 2019
)
0.8
" Because α-synuclein accumulation leads to a toxic gain of function, its ectopic expression in Drosophila has been a useful in vivo model for testing modifiers of its toxicity."( Monitoring α-Synuclein Proteotoxicity in Drosophila Models.
Szabo, A; Tofaris, GK, 2019
)
0.51
" PSMB9 knockdown aggravated accumulation of α-syn, degradation of TH, release of ROS, increased level of MDA, decreased level of GSH and eventually promoted apoptosis in SH-SY5Y cells after rotenone treatment, while over-expression of PSMB9 could attenuate these toxic effects of rotenone."( Activation of the immunoproteasome protects SH-SY5Y cells from the toxicity of rotenone.
Chen, S; Liu, Y; Mo, M; Song, C; Sun, C; Wang, X; Wang, Y; Yu, W, 2019
)
0.51
" Notably, we found that E46K, H50Q, G51D, and A53T αSyn-expressing flies showed earlier onset of locomotor dysfunction than WT αSyn-expressing flies, suggesting their enhanced toxic effects."( E46K mutant α-synuclein is more degradation resistant and exhibits greater toxic effects than wild-type α-synuclein in Drosophila models of Parkinson's disease.
Baba, K; Hayakawa, H; Minakawa, EN; Mochizuki, H; Nagai, Y; Sakai, R; Suzuki, M; Takeuchi, T; Ueyama, M, 2019
)
0.51
"Hsp104 is an AAA+ protein disaggregase, which can be potentiated via diverse mutations in its autoregulatory middle domain (MD) to mitigate toxic misfolding of TDP-43, FUS, and α-synuclein implicated in fatal neurodegenerative disorders."( Mining Disaggregase Sequence Space to Safely Counter TDP-43, FUS, and α-Synuclein Proteotoxicity.
Carman, PJ; Gambogi, C; Gates, SN; Gurpinar, E; Hernandez Murillo, OA; Hesketh, CD; Jackrel, ME; Lin, J; Mack, KL; Rizo, AN; Shorter, J; Southworth, DR; Stillman, J; Sudesh, S; Sweeny, EA; Tariq, A; Weitzman, R; Yee, K; Yokom, AL, 2019
)
0.51
" In yeast system, AGK2 enhances autophagy to clear toxic α-synuclein aggregates in an autophagy dependent manner."( A small molecule autophagy inducer exerts cytoprotection against α-synuclein toxicity.
Manjithaya, R; Suresh, SN, 2019
)
0.51
" Follow-up studies demonstrated that inhibition of Pah1 activity ameliorates the toxic effects of α-Syn, indicate that the diacylglycerol branch of lipid metabolism could enhance α-Syn neuronal cytotoxicity, and suggest a link between α-Syn toxicity and the biology of lipid droplets."( Proteomics-Based Monitoring of Pathway Activity Reveals that Blocking Diacylglycerol Biosynthesis Rescues from Alpha-Synuclein Toxicity.
Beyer, A; Boersema, PJ; Charmpi, K; Gerez, JA; Lampert, F; Malinovska, L; Peter, M; Picotti, P; Prymaczok, NC; Riek, R; Soste, M; van Oostrum, M; Vanni, S, 2019
)
0.73
" It is found that brazilin directly interacts with α-syn pentamer, and the hydrophobic interactions are favorable for brazilin binding with the α-syn pentamer, while the electrostatic part provides adverse effects."( Brazilin Inhibits α-Synuclein Fibrillogenesis, Disrupts Mature Fibrils, and Protects against Amyloid-Induced Cytotoxicity.
Chen, B; Jia, L; Liu, F; Lu, F; Sang, J; Wang, Y; Wei, W; Zhao, F; Zhao, W, 2019
)
0.51
"Alpha-synuclein (αS) fibrils are toxic to cells and contribute to the pathogenesis and progression of Parkinson's disease and other synucleinopathies."( Increased Dynamics of α-Synuclein Fibrils by β-Synuclein Leads to Reduced Seeding and Cytotoxicity.
Baum, J; Mouradian, MM; Williams, JK; Yan, R; Yang, X, 2019
)
1.96
" This work reports identification of the catabolic pathway of oligomeric α-synuclein as well as showing how Omi functions as the key molecule in the recognition and degradation of toxic oligomeric α-synuclein, a possible cause of neurodegeneration in PD, without affecting monomeric α-synuclein which is a native essential molecule for the normal function of neurons."( Neuroprotective function of Omi to α-synuclein-induced neurotoxicity.
Chung, HJ; Hong, ST; Islam, MS; Rahman, MM, 2020
)
0.56
" All pathogenic proteins differ from each other in biological function, primary sequences, and morphologies; however, the proteins are toxic when aggregated."( Aggregation and Cellular Toxicity of Pathogenic or Non-pathogenic Proteins.
Al Adem, K; Choi, MC; Kim, TY; Lee, S; Lukman, S, 2020
)
0.56
" Moreover, Tubastatin A significantly inhibited the expression of a toxic form of alpha-synuclein that is phosphorylated at serine position 129."( Inhibition of HDAC6 activity protects dopaminergic neurons from alpha-synuclein toxicity.
Francelle, L; Outeiro, TF; Rappold, GA, 2020
)
1.02
" All patients experienced at least one adverse event, but most of them were considered unrelated to study treatment (except for transient local injection site reactions, which affected all but one patient)."( Safety and immunogenicity of the α-synuclein active immunotherapeutic PD01A in patients with Parkinson's disease: a randomised, single-blinded, phase 1 trial.
El-Agnaf, O; Galabova, G; Kutzelnigg, A; Lührs, P; Mairhofer, A; Majbour, N; Medori, R; Mihailovska, E; Poewe, W; Schneeberger, A; Schwenke, C; Staffler, G; Thun-Hohenstein, C; Vaikath, N; Volc, D; Winter, D, 2020
)
0.56
"Repeated administrations of PD01A were safe and well tolerated over an extended period."( Safety and immunogenicity of the α-synuclein active immunotherapeutic PD01A in patients with Parkinson's disease: a randomised, single-blinded, phase 1 trial.
El-Agnaf, O; Galabova, G; Kutzelnigg, A; Lührs, P; Mairhofer, A; Majbour, N; Medori, R; Mihailovska, E; Poewe, W; Schneeberger, A; Schwenke, C; Staffler, G; Thun-Hohenstein, C; Vaikath, N; Volc, D; Winter, D, 2020
)
0.56
"Aggrephagy is a selective autophagic degradation intracellular mechanism that clears toxic misfolded protein aggregates such as α-synuclein."( XCT 790 is a pharmacological aggrephagy inducer in a yeast model of proteotoxicity.
Jayaprakash Rao, M; Manjithaya, R; Suresh, SN, 2021
)
0.62
" Together, these data suggested that α-synuclein PFFs are toxic in functional lysosomes in vitro."( Fibrillar α-synuclein toxicity depends on functional lysosomes.
Adlard, PA; Ayton, S; Bush, AI; Finkelstein, DI; Guiney, SJ; Lei, P; Mawal, CH, 2020
)
0.56
" NI-hADSC-CM treatment enhanced the TH expression, stabilized α-syn monomers, reduced the levels of toxic insoluble p-S129 α-syn, improved the expression of neuronal functional proteins, regulated the Bax/Bcl-2 ratio, and upregulated the expression of pro-caspases, along with PARP-1 inactivation."( Neural-Induced Human Adipose Tissue-Derived Stem Cells Conditioned Medium Ameliorates Rotenone-Induced Toxicity in SH-SY5Y Cells.
Jang, S; Jeong, HS; Ramalingam, M, 2021
)
0.62
" We discovered that a safe food additive, fast green FCF, is capable of inhibiting α-synuclein fibrillogenesis and reducing the related cytotoxicity."( The food additive fast green FCF inhibits α-synuclein aggregation, disassembles mature fibrils and protects against amyloid-induced neurotoxicity.
Jiang, L; Liu, F; Lu, F; Sang, J; Wang, F; Wang, W; Wang, X; Wang, Y, 2021
)
0.62
" All patients experienced at least one adverse event."( Safety and Tolerability of Active Immunotherapy Targeting α-Synuclein with PD03A in Patients with Early Parkinson's Disease: A Randomized, Placebo-Controlled, Phase 1 Study.
Bürger, V; deMarzi, R; Djamshidian, A; Galabova, G; Heim, B; Kutzelnigg, A; Lührs, P; Mangesius, S; Medori, R; Meissner, WG; Poewe, W; Rascol, O; Riha, C; Schneeberger, A; Seppi, K; Staffler, G; Stolz, R; Thun-Hohenstein, C; Volc, D; Wachowicz, K, 2021
)
0.62
" Although this effect occurs with the formation of differently toxic products, the molecular basis of this inhibition is still unclear."( Structural Features and Toxicity of α-Synuclein Oligomers Grown in the Presence of DOPAC.
Acquasaliente, L; Bucciantini, M; Fongaro, B; Leri, M; Palazzi, L; Polverino de Laureto, P; Stefani, M, 2021
)
0.62
" We report that SCD inhibitors are toxic to early human and rat neuron cultures while displaying minimal toxicity to late cultures."( SCD Inhibition Protects from α-Synuclein-Induced Neurotoxicity But Is Toxic to Early Neuron Cultures.
Bennion, M; Carlile, TM; Dalkilic-Liddle, I; Dhokai, S; Groot, J; Hirst, WD; Hrdlicka, L; Nicholatos, JW; Tran, D; Weihofen, A,
)
0.13
" Results showed no treatment-related adverse findings and the no-observed-adverse-effect-level was the highest dose tested."( Nonclinical safety evaluation, pharmacokinetics, and target engagement of Lu AF82422, a monoclonal IgG1 antibody against alpha-synuclein in development for treatment of synucleinopathies.
Christiansen, J; Ditlevsen, DK; Fjord-Larsen, L; Kaarde, M; Larsen, F; Schrøder-Hansen, LM; Thougaard, A; Wegener, KM,
)
0.34
" Such soluble oligomers are believed to be key toxic species in the related disorders; therefore, identification of the structural determinants of toxicity is of upmost importance."( The Pathological G51D Mutation in Alpha-Synuclein Oligomers Confers Distinct Structural Attributes and Cellular Toxicity.
Castellana-Cruz, M; Chen, SW; Cremades, N; Dobson, CM; Du, Z; Itzhaki, LS; Knowles, TPJ; Kumita, JR; Levin, A; Mannini, B; Meisl, G; Xu, CK, 2022
)
1
" A large variety of experimental evidences supported the idea that soluble oligomeric species of different proteins might be more toxic than the larger fibrillar forms."( Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies.
Bigi, A; Cascella, R; Cecchi, C; Cremades, N, 2022
)
0.72
" Accordingly, the inhibition of αSN fibrillation and elimination of toxic aggregates are the main therapeutic strategies."( Insights into the inhibitory mechanism of skullcapflavone II against α-synuclein aggregation and its mediated cytotoxicity.
Aliakbari, F; Bardania, H; Farhadpour, M; Hourfar, H; Mohammadi, M; Morshedi, D; Najarzadeh, Z; Parsafar, S; Seyedfatemi, SS, 2022
)
0.72
" Finally, using human induced pluripotent stem cell (iPSC)-derived neurons, we showed that amplified α-SYN aggregates from AD + LB brain of patients with APOE4 were highly toxic to neurons, whereas the same amount of α-SYN monomer was not toxic."( APOE4 exacerbates α-synuclein seeding activity and contributes to neurotoxicity in Alzheimer's disease with Lewy body pathology.
Amerna, D; Bu, G; Burgess, JD; DeTure, MA; Dickson, DW; Heckman, MG; Ikezu, TC; Jin, Y; Kondru, NC; Li, F; Li, Z; Martens, YA; McLean, PJ; O'Leary, J; Qiao, W; Ross, OA; Sonoustoun, B; Zhao, J; Zhao, N, 2022
)
0.72
" The truncated protein is more toxic to mitochondria than full-length protein and diminishes the effect of PDI on α-syn fibrillation."( C-terminal truncation modulates α-Synuclein's cytotoxicity and aggregation by promoting the interactions with membrane and chaperone.
Jiang, L; Li, C; Liu, M; Liu, X; Pei, Y; Pielak, GJ; Xu, L; Zhang, C; Zhang, Z; Zhou, X, 2022
)
0.72
" Therefore, this study investigated the capacity of the metabolites 3,4-dihydroxyphenylacetaldehyde (DOPAL), 4-hydroxy-3-methoxyphenylethanol (MOPET), and 3-methoxy-4-hydroxyphenylacetaldehyde (MOPAL) to prevent the aggregation and toxic effects of αsyn fibrils."( Hydroxytyrosol and dopamine metabolites: Anti-aggregative effect and neuroprotective activity against α-synuclein-induced toxicity.
Cerezo, AB; Gallardo-Fernández, M; Garcia-Parrilla, MC; Hornedo-Ortega, R; Troncoso, AM, 2023
)
0.91
" However, dopamine can interact with αSyn and produce oligomeric species which were reported to be toxic in many models."( Dopamine-Induced Oligomers of α-Synuclein Inhibit Amyloid Fibril Growth and Show No Toxicity.
Borisova, T; Galkin, M; Priss, A; Shvadchak, VV; Topcheva, O, 2023
)
0.91
" Under pathological conditions known as injection amyloidosis and Parkinson's disease, these proteins aggregate forming amyloid oligomers and fibrils, toxic species that exert high cell toxicity."( Unsaturated fatty acids uniquely alter aggregation rate of α-synuclein and insulin and change the secondary structure and toxicity of amyloid aggregates formed in their presence.
Kurouski, D; Matveyenka, M; Zhaliazka, K, 2023
)
0.91
" In the current investigation we produced two distinct classes of aS oligomer of differed protein conformation, stability and compared their toxic nature to cultured neuronal cells."( Structure specific neuro-toxicity of α-synuclein oligomer.
Bhattacharjee, A; Das, L; Dhabal, S; Dolui, S; Kundu, S; Maiti, NC; Mondal, A, 2023
)
0.91
" In PD pathogenesis, alpha-Synuclein (α-Syn) loses its native structure, triggering a polymerization cascade that leads to the formation of toxic inclusions, the PD hallmark."( Uncovering the Role of Natural and Synthetic Small Molecules in Counteracting the Burden of α-Synuclein Aggregates and Related Toxicity in Different Models of Parkinson's Disease.
Mohammed, S; Ramazzina, I; Russo, I, 2023
)
1.23

Pharmacokinetics

ExcerptReferenceRelevance
" A single dose pharmacokinetic (PK) study in cynomolgus monkeys with dose levels of 1-30 mg/kg confirmed PK properties in the expected range for a mAb with a soluble target, and target engagement was shown as a decrease in free alpha-synuclein in plasma."( Nonclinical safety evaluation, pharmacokinetics, and target engagement of Lu AF82422, a monoclonal IgG1 antibody against alpha-synuclein in development for treatment of synucleinopathies.
Christiansen, J; Ditlevsen, DK; Fjord-Larsen, L; Kaarde, M; Larsen, F; Schrøder-Hansen, LM; Thougaard, A; Wegener, KM,
)
0.52

Compound-Compound Interactions

ExcerptReferenceRelevance
" In this study we have examined the effects of four naturally occurring polyphenols in combination with β-cyclodextrin (β-CD) on the aggregation of α-synuclein in the presence of macromolecular crowding agents."( Polyphenols in combination with β-cyclodextrin can inhibit and disaggregate α-synuclein amyloids under cell mimicking conditions: A promising therapeutic alternative.
Batra, R; Chowdhury, PK; Gautam, S; Karmakar, S; Kundu, B; Pradhan, P; Sharma, P; Singh, J, 2017
)
0.46
" Our study provides recommendations for analysis of neurogranin trunc P75, α-synuclein, and tau, in combination with the ratio of β-amyloid Aβ(1-42)/Aβ(1-40)."( Recommendations for cerebrospinal fluid collection for the analysis by ELISA of neurogranin trunc P75, α-synuclein, and total tau in combination with Aβ(1-42)/Aβ(1-40).
Coart, E; Demeyer, L; François, C; Hansson, O; Herbst, V; Janelidze, S; Mauroo, K; Stoops, E; Vanderstichele, H, 2017
)
0.46

Bioavailability

ExcerptReferenceRelevance
" It is highly lipophylic and poorly absorbed in the gastrointestinal tract (11)."( Oral administration of rotenone using a gavage and image analysis of alpha-synuclein inclusions in the enteric nervous system.
Funk, RH; Pan-Montojo, FJ, 2010
)
0.6
" Anle138b had no detectable toxicity at therapeutic doses and an excellent oral bioavailability and blood-brain-barrier penetration."( Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease.
Bähr, M; Bertsch, U; Bötzel, K; Deeg, AA; Eiden, M; Frank, T; Geissen, M; Giese, A; Griesinger, C; Groschup, M; Hirschberger, T; Krauth, JJ; Kretzschmar, H; Leidel, F; Leonov, A; Levin, J; Mitteregger-Kretzschmar, G; Pan-Montojo, F; Pilger, J; Prix, C; Ryazanov, S; Samwer, M; Schmidt, F; Shi, S; Tavan, P; Teichmann, U; Uhr, M; Urlaub, H; Wagner, J; Weishaupt, JH; Zinth, W; Zweckstetter, M, 2013
)
0.39
" The present study involves formulation of curcumin and piperine coloaded glyceryl monooleate (GMO) nanoparticles coated with various surfactants with a view to enhance the bioavailability of curcumin and penetration of both drugs to the brain tissue crossing the BBB and to enhance the anti-parkinsonism effect of both drugs in a single platform."( Delivery of Dual Drug Loaded Lipid Based Nanoparticles across the Blood-Brain Barrier Impart Enhanced Neuroprotection in a Rotenone Induced Mouse Model of Parkinson's Disease.
Das, M; Kundu, P; Sahoo, SK; Tripathy, K, 2016
)
0.43
" However, this tannin interacts very strongly with human serum albumin, significantly reducing the bioavailability of this compound."( Interaction of α-synuclein with Rhus typhina tannin - Implication for Parkinson's disease.
Abdulladjanova, N; Bryszewska, M; Ionov, M; Makhmudov, R; Mavlyanov, S; Milowska, K; Sekowski, S; Zamaraeva, M, 2017
)
0.46
" These studies demonstrated that NPT200-11 is orally bioavailable and brain penetrating and established target plasma and brain exposures for future studies of potential therapeutic benefit."( The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson's disease.
Bonhaus, D; Khan, A; Koike, MA; Masliah, E; Price, DL; Rockenstein, E; Wrasidlo, W, 2018
)
0.81
" Since every person harbors a unique set of gut bacteria, we investigated the influence of the gut microbiota's interpersonal heterogeneity on the production and bioavailability of flavonoid metabolites that may interfere with the misfolding of alpha (α)-synuclein, a process that plays a central role in Parkinson's disease and other α-synucleinopathies."( Heterogeneity in gut microbiota drive polyphenol metabolism that influences α-synuclein misfolding and toxicity.
Brathwaite, J; Carry, E; Faith, J; Frolinger, T; Hao, K; Ho, L; Lloyd, TE; Mazzola, P; Mogno, I; Ono, K; Pasinetti, GM; Ruan, K; Simon, JE; Sims, S; Tsuji, M; Westfall, S; Wu, Q; Zhao, D, 2019
)
0.51
" ATH434 is a novel, orally bioavailable brain penetrant small molecule inhibitor of α-syn aggregation."( ATH434 Reduces α-Synuclein-Related Neurodegeneration in a Murine Model of Multiple System Atrophy.
Bradbury, M; Heras-Garvin, A; Malfertheiner, K; Refolo, V; Schmidt, C; Stamler, D; Stefanova, N; Wenning, GK, 2021
)
0.62
" Here, we report that proteotoxicity in yeast and Drosophila models for Parkinson's disease can be prevented by increasing the bioavailability of Ca2+, which adjusts intracellular Ca2+ handling and boosts lysosomal proteolysis."( Ca2+ administration prevents α-synuclein proteotoxicity by stimulating calcineurin-dependent lysosomal proteolysis.
Aufschnaiter, A; Broeskamp, F; Büttner, S; de Ory, A; Diessl, J; Eisenberg, T; Habernig, L; Peselj, C; Urbauer, E, 2021
)
0.62
" Small aggregates (oligomers) of α-synuclein have been shown to be the most relevant neurotoxic species and are targeted by anle138b, an orally bioavailable small molecule compound which shows strong disease-modifying effects in animal models of synucleinopathies."( Safety, tolerability and pharmacokinetics of the oligomer modulator anle138b with exposure levels sufficient for therapeutic efficacy in a murine Parkinson model: A randomised, double-blind, placebo-controlled phase 1a trial.
Dalley, JW; Giese, A; Griesinger, C; Langer, S; Leonov, A; Levin, J; Mariner, C; Matthias, T; Melbourne, S; Morgan, A; Prager, K; Ryazanov, S; Schmidt, F; Sing, N; Spillantini, MG; Weckbecker, D; Wegrzynowicz, M, 2022
)
0.72
" Rotenone was not detectable in plasma at a lower limit of quantification of 2 ng/mL (5 nM), showing that oral rotenone had insufficient bioavailability to achieve sustained systemic drug levels in mice."( Non-Reproducibility of Oral Rotenone as a Model for Parkinson's Disease in Mice.
Gurke, R; Manderscheid, C; Niederberger, E; Schreiber, Y; Tegeder, I; Wilken-Schmitz, A, 2022
)
0.72
" Given the potential role of c-Abl in PD, a c-Abl inhibitor library was developed to identify orally bioavailable c-Abl inhibitors capable of crossing the blood-brain barrier based on predefined characteristics, leading to the discovery of IkT-148009."( The c-Abl inhibitor IkT-148009 suppresses neurodegeneration in mouse models of heritable and sporadic Parkinson's disease.
Bisen, S; Brahmachari, S; Dang, B; Dawson, TM; Dawson, VL; Karuppagounder, SS; Kelly, T; Kim, E; Kumar, M; Lee, HW; Marino Lee, S; Nguyen, R; Rush, R; Sigmon, A; Sloan, N; Wang, H; Watkins, L; Werner, MH; Yamashita, Y, 2023
)
0.91
" The pharmacokinetic and tissue distribution studies of the formulation in rats showed a significant improvement in the kinetic parameters when compared to naïve FMT, further the formulation also improved the brain bioavailability of FMT."( Polysorbate 80 surface modified SLNs of formoterol suppress SNCA gene and mitochondrial oxidative stress in mice model of Parkinson's disease.
Garikapati, KK; Krishnamurthy, PT; Kumari, M; Sola, P, 2023
)
0.91

Dosage Studied

Alpha-synuclein (SNCA) is a major risk gene for Parkinson's disease (PD) Increased SNCA gene dosage results in a parkinsonian syndrome in affected families.

ExcerptRelevanceReference
" However, behavior analysis showed a progressive reduction of spontaneous vertical motor activity in both mutant lines correlating with the dosage of overexpression."( Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence of aggregate formation.
Auburger, G; Bernard, DJ; Braak, H; Chen, A; Del Turco, D; Deller, T; Garrett, L; Gispert, S; Hamm-Clement, J; Korf, HW; Nussbaum, RL, 2003
)
0.58
" Two different mutations in the alpha-synuclein gene as well as increased gene dosage of wild-type alpha-synuclein all associate with early onset cases of PD; and transgenic animal models overexpressing alpha-synuclein develop PD symptoms."( Inhibiting aggregation of alpha-synuclein with human single chain antibody fragments.
Emadi, S; Liu, R; Lyubchenko, Y; McAllister, C; Messer, A; Schulz, P; Sierks, MR; Yuan, B, 2004
)
0.91
" These findings suggest a direct relation between SNCA gene dosage and disease progression."( Alpha-synuclein locus duplication as a cause of familial Parkinson's disease.
Amouyel, P; Andrieux, J; Chartier-Harlin, MC; Defebvre, L; Destée, A; Douay, X; Farrer, M; Hulihan, M; Kachergus, J; Larvor, L; Levecque, C; Lincoln, S; Mouroux, V; Roumier, C; Waucquier, N,
)
1.57
" These results indicate that SNCA is more frequently associated with familial Parkinson's disease than previously thought, and that there is a clear dosage effect according to the number of supernumerary copies of this gene."( Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease.
Agid, Y; Bonnet, AM; Brice, A; Débarges, B; Dürr, A; Ibáñez, P; Lohmann, E; Pollak, P; Tison, F,
)
0.44
"We searched for alterations of alpha-synuclein gene dosage and analysed the entire coding region for point mutations in 54 dementia with Lewy body disease (DLB) and in 103 young onset Parkinson's disease (PD) patients from Central Europe."( The role of alpha-synuclein gene multiplications in early-onset Parkinson's disease and dementia with Lewy bodies.
Asmus, F; Behnke, S; Berg, D; Bonelli, SB; Ceballos-Baumann, A; Gasser, T; Haussermann, P; Hofer, A; Krüger, R; Niwar, M; Prestel, J; Ransmayr, G; Riemenschneider, M; Riess, O; Sharma, M; Steffelbauer, M; Zimprich, A, 2005
)
0.99
"We could not detect any quantitative alterations in the gene dosage of alpha-synuclein."( The role of alpha-synuclein gene multiplications in early-onset Parkinson's disease and dementia with Lewy bodies.
Asmus, F; Behnke, S; Berg, D; Bonelli, SB; Ceballos-Baumann, A; Gasser, T; Haussermann, P; Hofer, A; Krüger, R; Niwar, M; Prestel, J; Ransmayr, G; Riemenschneider, M; Riess, O; Sharma, M; Steffelbauer, M; Zimprich, A, 2005
)
0.94
"To determine whether a triplication or some other dosage alteration in the alpha-synuclein gene is present in one or more patients with familial PD in a large multinational collective."( Failure to find alpha-synuclein gene dosage changes in 190 patients with familial Parkinson disease.
Auburger, G; Gispert, S; Kostic, V; Mota-Vieira, L; Trenkwalder, C, 2005
)
0.9
"Alpha-synuclein gene dosage values measured with real-time polymerase chain reaction."( Failure to find alpha-synuclein gene dosage changes in 190 patients with familial Parkinson disease.
Auburger, G; Gispert, S; Kostic, V; Mota-Vieira, L; Trenkwalder, C, 2005
)
2.12
"Alterations in alpha-synuclein gene dosage are rare in familial PD."( Failure to find alpha-synuclein gene dosage changes in 190 patients with familial Parkinson disease.
Auburger, G; Gispert, S; Kostic, V; Mota-Vieira, L; Trenkwalder, C, 2005
)
1.03
" There was no difference in the alpha-synuclein gene dosage between PD patients with high and low mRNA expression."( Alpha-synuclein mRNA expression in sporadic Parkinson's disease.
Chandran, VR; Fook-Chong, S; Shen, H; Tan, EK; Teoh, ML; Yew, K; Yuen, Y; Zhao, Y, 2005
)
2.05
" Two recent publications of alpha-synuclein-duplication mutations show that the severity of familial Parkinsonian phenotype is dependent upon SNCA gene dosage and corresponding protein levels."( Gene dosage and pathogenesis of Parkinson's disease.
Eriksen, JL; Petrucelli, L; Przedborski, S, 2005
)
0.62
" Kaplan-Meier analysis also supported a dosage effect of Rep1 allele 2 on age at onset."( Association of alpha-synuclein Rep1 polymorphism and Parkinson's disease: influence of Rep1 on age at onset.
Aggelakis, K; Gourbali, V; Hadjigeorgiou, GM; Papadimitriou, A; Scarmeas, N; Singleton, A; Xiromerisiou, G, 2006
)
0.69
" SNCA gene dosage analysis was also performed for AdPD using quantitative duplex polymerase chain reaction of genomic DNA."( Screening for SNCA and LRRK2 mutations in Greek sporadic and autosomal dominant Parkinson's disease: identification of two novel LRRK2 variants.
Gourbali, V; Hadjigeorgiou, GM; Johnson, J; Papadimitriou, A; Papakonstantinou, I; Singleton, AB; Xiromerisiou, G, 2007
)
0.34
" In this PD model, insoluble deposits of Ser129-phosphorylated alpha-synuclein(A53T) are negatively correlated with the dosage of Sept4."( Sept4, a component of presynaptic scaffold and Lewy bodies, is required for the suppression of alpha-synuclein neurotoxicity.
Hagiwara, A; Hattori, N; Hikawa, R; Ihara, M; Kinoshita, M; Kitano, A; Miyakawa, T; Mori, H; Noda, M; Takanashi, M; Tanigaki, A; Tomimoto, H; Yamasaki, N, 2007
)
0.8
" A gene dosage effect is observed in some cases, and the phenotype of some of the mutation carriers closely resembles typical PD."( Pathogenic mutations in Parkinson disease.
Skipper, LM; Tan, EK, 2007
)
0.34
" MLPA (Multiplex Ligation-dependent Probe Amplification), is a cheap, simple, rapid, and sensitive tool to detect exon dosage alterations and specific point mutations in selected genes."( Multiplex ligation-dependent probe amplification assay for simultaneous detection of Parkinson's disease gene rearrangements.
Brancati, F; Dallapiccola, B; De Angelis, MV; Ferraris, A; Garavaglia, B; Palka, G; Scarciolla, O; Stuppia, L; Uncini, A; Valbonesi, S; Valente, EM, 2007
)
0.34
" All genes were sequenced bi-directionally, and, additionally, SNCA, PRKN and PINK1 were subjected to gene dosage analysis."( Analysis of Parkinson disease patients from Portugal for mutations in SNCA, PRKN, PINK1 and LRRK2.
Bras, J; Calado, A; Dias, M; Guerreiro, R; Hardy, J; Januario, C; Morgadinho, A; Oliveira, C; Ribeiro, M; Semedo, C; Singleton, A, 2008
)
0.35
"To determine the genetic, biochemical, and neuropathologic characteristics of patients with autopsy-confirmed autosomal dominant Lewy body disease, with particular reference to the dosage effects of SNCA."( Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia.
Idezuka, J; Ikeuchi, T; Ishikawa, A; Iwatsubo, T; Kakita, A; Kaneko, H; Kasuga, K; Nishizawa, M; Onodera, O; Shiga, A; Takahashi, H; Tan, CF; Wakabayashi, K, 2008
)
0.35
" The homozygous patient demonstrated the most severe phenotype, suggesting that SNCA dosage has a considerable effect on disease phenotype even within a family."( Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia.
Idezuka, J; Ikeuchi, T; Ishikawa, A; Iwatsubo, T; Kakita, A; Kaneko, H; Kasuga, K; Nishizawa, M; Onodera, O; Shiga, A; Takahashi, H; Tan, CF; Wakabayashi, K, 2008
)
0.35
"The severity of clinical presentation is correlated with SNCA dosage and does not appear to be overtly affected by the presence of other genes in the multiplicated region."( Genomic investigation of alpha-synuclein multiplication and parkinsonism.
Adler, CH; Braithwaite, AT; Chartier-Harlin, MC; Farrer, MJ; Fuchs, J; Gasser, T; Gwinn, K; Hattori, N; Hulihan, MM; Kachergus, J; Langston, JW; Larvor, L; Maraganore, DM; Middleton, FA; Nilsson, C; Nishioka, K; Ross, OA; Skipper, LM, 2008
)
0.65
"SNCA dosage is responsible for parkinsonism, autonomic dysfunction, and dementia observed within each family."( Genomic investigation of alpha-synuclein multiplication and parkinsonism.
Adler, CH; Braithwaite, AT; Chartier-Harlin, MC; Farrer, MJ; Fuchs, J; Gasser, T; Gwinn, K; Hattori, N; Hulihan, MM; Kachergus, J; Langston, JW; Larvor, L; Maraganore, DM; Middleton, FA; Nilsson, C; Nishioka, K; Ross, OA; Skipper, LM, 2008
)
0.65
"Increased alpha-synuclein gene (SNCA) dosage due to locus multiplication causes autosomal dominant Parkinson's disease (PD)."( GATA transcription factors directly regulate the Parkinson's disease-linked gene alpha-synuclein.
Bresnick, EH; Eklund, AC; Grass, JA; Liao, Z; McGoldrick, M; Mollenhauer, B; Ney, PA; Ng, J; Pepivani, I; Scherzer, CR; Schlossmacher, MG; Zheng, B, 2008
)
0.97
" Gene dosage change of the aforementioned genes was studied using multiple ligation-dependent probe amplification."( Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease.
Baik, JS; Choi, JM; Chung, SJ; Kang, SY; Kim, DH; Kim, JH; Kim, JS; Kim, JW; Kim, SJ; Kim, YJ; Lee, MC; Lee, MS; Lee, PH; Lyoo, CH; Ma, HI; Park, MY; Shin, HW; Sohn, YH; Sung, YH; Woo, MS; Yong, SW, 2008
)
0.35
" Gene dosage analyses were conducted in screening of MAPT, alpha-synuclein, TDP-43 (or TARDBP), GSK3beta, and parkin."( Mutation analyses in amyotrophic lateral sclerosis/parkinsonism-dementia complex of the Kii peninsula, Japan.
Funayama, M; Hattori, N; Imamichi, Y; Kokubo, Y; Kuzuhara, S; Li, Y; Mizuno, Y; Sasaki, R; Tomiyama, H, 2008
)
0.59
" A total of 187 unrelated Dutch EOPD patients (age at onset < or = 50 years) were phenotyped and screened for mutations in all exons of Parkin, DJ-1, and PINK1 by direct sequencing and gene dosage analysis."( Genotypic and phenotypic characteristics of Dutch patients with early onset Parkinson's disease.
Anar, B; Fang, Y; Groen, JL; Heutink, P; Macedo, MG; Rizzu, P; Uras, A; van Hilten, JJ; van Rooden, SM; Verbaan, D; Visser, M, 2009
)
0.35
" elegans DA neurons results in dosage and age-dependent neurodegeneration."( Application of a C. elegans dopamine neuron degeneration assay for the validation of potential Parkinson's disease genes.
Berkowitz, LA; Caldwell, GA; Caldwell, KA; Hamamichi, S; Harrington, AJ; Knight, AL, 2008
)
0.35
"Patients were screened by the exon dosage of the SNCA gene."( Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms.
Agid, Y; Bonnet, AM; Brefel-Courbon, C; Brice, A; Destée, A; Durif, F; Dürr, A; Heath, S; Ibáñez, P; Janin, S; Lesage, S; Lohmann, E; Zelenika, D, 2009
)
1.8
" Genotyping and dosage analyses showed that the multiplied regions were variable in size (0."( Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms.
Agid, Y; Bonnet, AM; Brefel-Courbon, C; Brice, A; Destée, A; Durif, F; Dürr, A; Heath, S; Ibáñez, P; Janin, S; Lesage, S; Lohmann, E; Zelenika, D, 2009
)
1.8
" Also, alpha-syn gene dosage can cause familial PD and inhibition of its gene expression by blocking translation via a newly identified Iron Responsive Element-like RNA sequence in its 5'-untranslated region may provide a new PD drug target."( Physiological and pathological role of alpha-synuclein in Parkinson's disease through iron mediated oxidative stress; the role of a putative iron-responsive element.
Branden, L; Greig, NH; Huang, X; Olivares, D; Rogers, JT, 2009
)
0.62
" Within our cohort, one affected individual from each of 92 multiplex PD families showing the greatest evidence of linkage to the region around SNCA was screened for dosage alterations and sequence changes; no dosage or non-synonymous sequence changes were found."( Alpha-synuclein and familial Parkinson's disease.
Elsaesser, VE; Foroud, T; Halter, CA; Marek, DK; Nichols, WC; Pankratz, N; Pauciulo, MW; Pfeiffer, RF; Rudolph, A; Wojcieszek, J, 2009
)
1.8
" No mutations involving the examined exons dosage were revealed in alpha-synuclein gene."( [Analysis of the alpha-synuclein gene dosage variation associated with autosomal dominant form of ParkinsonTs disease].
Bagyeva, GKh; Illarioshkin, SN; Ivanova-Smolenskaia, IA; Karabanov, AV; Limborskaia, SA; Semenova, EV; Shadrina, MI; Slominskiĭ, PA, 2009
)
0.93
" We investigated whether alphaSyn gene dosage interacts with differences in phospholipid composition across brain regions or with age-related changes in brain phospholipid composition."( Lipidomic profiling in mouse brain reveals differences between ages and genders, with smaller changes associated with alpha-synuclein genotype.
Brown, HA; Ivanova, PT; Lavoie, MJ; Milne, SB; Myers, DS; Rappley, I; Selkoe, DJ, 2009
)
0.56
" Accumulated evidence emphasizes the importance of SNCA dosage and expression levels in PD pathogenesis."( Genetic regulation of alpha-synuclein mRNA expression in various human brain tissues.
Browndyke, JN; Burke, JR; Chiba-Falek, O; Cronin, KD; Ge, D; Hulette, CM; Linnertz, C; Saucier, L; Welsh-Bohmer, KA, 2009
)
0.67
" The multiplex ligation-dependent probe amplification method was used to detect exon dosage changes."( Analysis of exon dosage using MLPA in South African Parkinson's disease patients.
Bardien, S; Carr, J; Keyser, RJ; Lombard, D; Veikondis, R, 2010
)
0.36
"The protein alpha-synuclein accumulates in the brain of patients with sporadic Parkinson's disease (PD), and increased gene dosage causes a severe, dominantly inherited form of PD, but we know little about the effects of synuclein that precede degeneration."( Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis.
Berge, V; Chaudhry, FA; Edwards, RH; Lee, MK; Lu, W; Nakamura, K; Nemani, VM; Nicoll, RA; Onoa, B, 2010
)
1.05
" The amount of NT-modified aSN within PBMCs was positively correlated with intracellular ROS concentration and inversely related to daily dosage of levodopa, making its measurement potentially relevant for disease-intervention studies."( Alpha-synuclein nitration and autophagy response are induced in peripheral blood cells from patients with Parkinson disease.
Andreoni, S; Begni, B; Brighina, L; Difrancesco, JC; Ferrarese, C; Galbussera, A; Piazza, F; Piolti, R; Prigione, A, 2010
)
1.8
"Alpha-synuclein (SNCA) is a major risk gene for Parkinson's disease (PD), and increased SNCA gene dosage results in a parkinsonian syndrome in affected families."( Methylation regulates alpha-synuclein expression and is decreased in Parkinson's disease patients' brains.
Jowaed, A; Kaut, O; Schmitt, I; Wüllner, U, 2010
)
2.12
" Some mutation subtypes are likely underestimated because only few studies reported extensive mutation analyses of all five genes, by both exonic sequencing and dosage analyses."( Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update.
Cruts, M; Nuytemans, K; Theuns, J; Van Broeckhoven, C, 2010
)
0.36
" Accumulated evidence emphasizes the importance of SNCA dosage and expression levels in PD pathogenesis."( The effect of SNCA 3' region on the levels of SNCA-112 splicing variant.
Burke, JR; Chiba-Falek, O; Hulette, CM; Linnertz, C; McCarthy, JJ; Saucier, L; Welsh-Bohmer, KA, 2011
)
0.37
" The triplication of α-syn gene has been linked to early-onset familial PD, suggesting that the cellular dosage of α-syn is an important modulator of its toxicity."( Macroautophagy and the proteasome are differently involved in the degradation of alpha-synuclein wild type and mutated A30P in an in vitro inducible model (PC12/TetOn).
Albani, D; Batelli, S; Forloni, G; Peverelli, E; Rodilossi, S, 2011
)
0.6
" Exon dosage variations account for a high proportion of Parkinson's disease mutations, mainly for PARKIN gene."( Exon dosage variations in Brazilian patients with Parkinson's disease: analysis of SNCA, PARKIN, PINK1 and DJ-1 genes.
de Rosso, AL; José Silva, D; Junior, MC; Moura, KC; Nicaretta, DH; Pereira, JS; Pimentel, MM; Santos-Rebouças, CB, 2012
)
0.38
" However, the penetrance in families with SNCA duplication is as low as 30%, indicating that factors other than the SNCA gene dosage have an important role in neuronal death."( Increased expression of α-synuclein by SNCA duplication is associated with resistance to toxic stimuli.
Jeon, BS; Kim, HJ; Lee, KW; Park, SS; Yoon, MY, 2012
)
0.38
" In the patients with onset <50 years (n = 12), all parkin, PINK1, and DJ-1 exons were sequenced, and dosage analysis of parkin, PINK1, DJ-1, LRRK2, and SNCA was performed."( Analysis of LRRK2, SNCA, Parkin, PINK1, and DJ-1 in Zambian patients with Parkinson's disease.
Atadzhanov, M; Bonifati, V; Breedveld, GJ; Kelly, P; Musonda, ST; Oostra, BA; Quadri, M; Shawa, N; Simons, EJ; Yonova-Doing, E, 2012
)
0.38
" Our α-syn BAC tg mice could be a valuable tool to evaluate α-syn gene dosage effects in vivo."( α-Synuclein BAC transgenic mice as a model for Parkinson's disease manifested decreased anxiety-like behavior and hyperlocomotion.
Inoue, H; Kurisu, J; Miyakawa, T; Moriwaki, Y; Takahashi, M; Takahashi, R; Uemura, K; Yamakado, H; Yamasaki, N, 2012
)
0.38
"Mutations in, or elevated dosage of, SNCA, the gene for α-synuclein (α-syn), cause familial Parkinson's disease (PD)."( Striatal dopamine transmission is subtly modified in human A53Tα-synuclein overexpressing mice.
Auburger, G; Cragg, SJ; Gispert, S; Platt, NJ, 2012
)
0.38
"Alpha-synuclein (SNCA) is a major risk gene for Parkinson's disease (PD) and increased SNCA gene dosage results in a parkinsonian syndrome in affected families."( Variants in the 3'UTR of SNCA do not affect miRNA-433 binding and alpha-synuclein expression.
Becker, J; Becker, T; Khazneh, H; Klein, C; Kostic, VS; Kubisch, C; Ramirez, A; Schmitt, I; van Rooyen, JP; Volk, A; Wüllner, U, 2012
)
2.06
" Open-field behavioral deficits indicated by rigidity and reduced locomotor activity were induced by the dual administration of α-syn oligomers plus fibrils but not the oligomers by themselves under the 10-day dosing regimen."( Nasal inoculation with α-synuclein aggregates evokes rigidity, locomotor deficits and immunity to such misfolded species as well as dopamine.
Davidova, TV; Gruden, MA; Kucheryanu, VG; Morozova-Roche, LA; Sewell, RD; Sherstnev, VV; Yanamandra, K, 2013
)
0.39
"5% of our whole population) were identified with the A53T SNCA mutation, two with a heterozygote dosage mutation and one with a heterozygote point mutation in the Parkin gene, and seven patients (10."( Genetic assessment of familial and early-onset Parkinson's disease in a Greek population.
Antonellou, R; Athanassiadou, A; Bozi, M; Gasser, T; Hadjigeorgiou, GM; Kamakari, S; Leonardos, A; Malamis, G; Maniati, M; Michelakakis, H; Moraitou, M; Papadimitriou, A; Papadimitriou, D; Papageorgiou, SG; Stamboulis, E; Stefanis, L; Tagaris, G; Theofilopoulos, D; Vassilatis, DK, 2014
)
0.4
" Behavioral deficits at the end of the 14-day dosing regime and on day 28 (i."( Intranasal administration of alpha-synuclein aggregates: a Parkinson's disease model with behavioral and neurochemical correlates.
Davydova, TV; Fomina, VG; Gruden, MA; Kudrin, VS; Morozova-Roche, LA; Narkevich, VB; Sewell, RD; Wang, C, 2014
)
0.69
" Increased dosage of genes located within the duplicated region probably cannot increase disease risk and disease severity without the contribution of additional risk factors."( A 6.4 Mb duplication of the α-synuclein locus causing frontotemporal dementia and Parkinsonism: phenotype-genotype correlations.
Bhatia, KP; Giffin, N; Hardy, J; Hehir, J; Hernandez, DG; Holton, JL; Houlden, H; Kara, E; Kiely, AP; Love, S; Nacheva, E; Nalls, MA; Pandraud, A; Pittman, AM; Proukakis, C; Quinn, N; Rantell, K; Revesz, T; Singleton, AB, 2014
)
0.4
" Our results confirm that systemic 6-OHDA dosing to nonhuman primates induces cardiac sympathetic neurodegeneration and loss of catecholaminergic enzymes in the adrenal medulla, and suggests that this model can be used as a platform to evaluate disease-modifying strategies aiming to induce peripheral neuroprotection."( Cardiac sympathetic denervation in 6-OHDA-treated nonhuman primates.
Dilley, K; Emborg, ME; Joers, V; Jones, C; Rahman, S; Shultz, J; Simmons, H, 2014
)
0.4
"The common age-related neurodegeneration of Parkinson's disease can result from dominant causes like increased dosage of vesicle-associated alpha-synuclein (SNCA) or recessive causes like deficiency of mitophagy factor PINK1."( Potentiation of neurotoxicity in double-mutant mice with Pink1 ablation and A53T-SNCA overexpression.
Auburger, G; Brehm, N; Gispert, S; Kern, B; Roeper, J; Rüb, U; Seidel, K; Walter, M; Weil, J, 2015
)
0.62
" Behavioral deficits at the end of the 14-day dosing regime and on day 28 (i."( Noradrenergic and serotonergic neurochemistry arising from intranasal inoculation with α-synuclein aggregates which incite parkinsonian-like symptoms.
Davydova, TV; Fomina, VG; Gruden, MA; Kudrin, VS; Morozova-Roche, LA; Narkevich, VB; Sewell, RD; Wang, C, 2015
)
0.42
" We observed somewhat greater α-synuclein with the PON1-108T (lower paraoxonase enzyme) allele, and with ≥ 10 h of exposure to cholinesterase inhibiting insecticides in the preceding 30 days, but neither of these associations followed a clear dose-response pattern."( Blood α-synuclein in agricultural pesticide handlers in central Washington State.
Checkoway, H; Cook, TJ; Farin, FM; Hofmann, JN; Keifer, MC; Paulsen, M; Searles Nielsen, S; Simpson, CD; Zhang, J, 2015
)
0.42
" With very limited information regarding genetic mutations or alterations in gene dosage as a cause of MSA, the search for novel risk genes, which may be in the form of common variants or rare variants, is the logical nexus for MSA research."( Multiple system atrophy: the application of genetics in understanding etiology.
Federoff, M; Houlden, H; Schottlaender, LV; Singleton, A, 2015
)
0.42
"Male Wistar rats were subjected to continuous intraperitoneal dosing of salsolinol (200 mg/kg in total) with osmotic mini-pumps for either two or four weeks."( Neuropathic alterations of the myenteric plexus neurons following subacute intraperitoneal administration of salsolinol.
Bugajski, A; Gajda, M; Gil, K; Kurnik, M; Thor, P, 2015
)
0.42
"Mutations and duplication/triplication of the alpha-synuclein (αSyn)-coding gene have been found to cause familial Parkinson's disease (PD), while genetic polymorphisms in the region controlling the expression level and stability of αSyn have been identified as risk factors for idiopathic PD, pointing to the importance of wild-type (wt) αSyn dosage in the disease."( Mechanisms of alpha-synuclein action on neurotransmission: cell-autonomous and non-cell autonomous role.
Chieregatti, E; Emanuele, M, 2015
)
1.04
" We demonstrate that co-expression of aSyn and bSyn exacerbates cytotoxicity, due to increased dosage of toxic synuclein forms, and that they are able to form heterodimers in both yeast and in human cells."( Yeast reveals similar molecular mechanisms underlying alpha- and beta-synuclein toxicity.
Becker, S; Braus, GH; Favretto, F; Gerhardt, E; Magalhães, F; Outeiro, TF; Popova, B; Rosado-Ramos, R; Tenreiro, S; Zweckstetter, M, 2016
)
0.43
" Dosage mutations of exons in these genes were carried out by multiple ligation-dependent probe amplification."( The heterozygous A53T mutation in the alpha-synuclein gene in a Chinese Han patient with Parkinson disease: case report and literature review.
An, Y; Chen, C; Guan, RY; Luo, SS; Sun, YM; Wang, J; Wu, JJ; Xiong, WX, 2016
)
0.71
" To address this outstanding issue, we directly compared the neurotoxicity of human asyn against that of h-asyn(D70-83), h-bsyn as well as rat asyn using an adeno-associated viral vector to express these proteins in a dose-response study where the vector load was varied over two orders of magnitude."( Toxic effects of human and rodent variants of alpha-synuclein in vivo.
Buck, K; Kirik, D; Landeck, N, 2017
)
0.71
"Alterations in α-synuclein dosage lead to familial Parkinson's disease (PD), and its accumulation results in synucleinopathies that include PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA)."( α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies.
Krainc, D; Wong, YC, 2017
)
0.46
" The revolutionary therapeutic breakthrough was the introduction of high dosage levodopa therapy by George Cotzias in 1967."( The 200-year journey of Parkinson disease: Reflecting on the past and looking towards the future.
Fahn, S, 2018
)
0.48
" Such therapy was achieved with high dosage of GM1 and more effectively with lower doses of LIGA20, a membrane permeable analog of GM1."( Gangliosides, α-Synuclein, and Parkinson's Disease.
Ledeen, RW; Wu, G, 2018
)
0.48
" For example, apoptosis increases in BMECs following the treatment with higher dosed rSncb."( Age-related Beta-synuclein Alters the p53/Mdm2 Pathway and Induces the Apoptosis of Brain Microvascular Endothelial Cells In Vitro.
Böhm, MRR; Brockhaus, K; Melkonyan, H; Thanos, S, 2018
)
0.48
" Together, increased dosage of α-Syn resulting in α-Syn oligomerization causes axonal transport disruption and energy deficits, leading to synapse loss in human neurons."( α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies.
Brazdis, RM; Galasko, DR; Groemer, TW; Grosch, J; Hannappel, C; Havlicek, S; Krach, F; Krumbiegel, M; Masliah, E; Prots, I; Reis, A; Schlötzer-Schrehardt, U; Schütz, O; Simmnacher, K; Veber, V; Winkler, J; Winner, B; Wrasidlo, W; Xiang, W, 2018
)
0.48
" Low dosage exposure to permethrin during neonatal brain development (from postnatal day 6 to postnatal day 21) leads to dopamine decrease in rat striatum nucleus, oxidative stress and behavioural changes linked to the development of Parkinson's like neurodegeneration later in life."( Early impairment of epigenetic pattern in neurodegeneration: Additional mechanisms behind pyrethroid toxicity.
Bordoni, L; Fedeli, D; Gabbianelli, R; Galeazzi, R; Laudadio, E; López-Rodas, G; Massaccesi, L; Nasuti, C, 2019
)
0.51
" Devices such as continuous infusion pumps and new dosage forms have been developed to improve the treatment response to L-dopa."( [Current Status and Future Prospects of Therapeutic Development of Parkinson's Disease].
Mochizuki, H, 2020
)
0.56
" SNCA dosage increase did not influence the differentiation efficiency of mDANs and CPNs."( Demonstration of brain region-specific neuronal vulnerability in human iPSC-based model of familial Parkinson's disease.
Alecu, JE; Brazdis, RM; Brendler, A; Dahms, A; Lörentz, S; Marsch, D; Marxreiter, F; Prots, I; Roybon, L; Schneider, Y; Simmnacher, K; Winner, B; Xiang, W, 2020
)
0.56
"Oral dosing and brain activity of 5b were established in nontransgenic mice."( A Stearoyl-Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α-Synuclein Mice.
Cirka, H; Dettmer, U; Fanning, S; Hodgetts, K; Hronowski, X; Imberdis, T; Kalinichenko, LS; Lambrecht, V; Müller, CP; Nam, AY; Nuber, S; Rajsombath, MM; Selkoe, DJ; Wang, J; Weihofen, A; Winkler, J, 2021
)
0.62
" The compound was also well-tolerated in a first-in-human oral dosing study in healthy and older volunteers with a favorable, dose-dependent pharmacokinetic profile."( The Compound ATH434 Prevents Alpha-Synuclein Toxicity in a Murine Model of Multiple System Atrophy.
Adlard, PA; Barnham, KJ; Billings, JL; Cherny, RA; Finkelstein, DI; Saleh, E; Shukla, JJ; Stefanova, N, 2022
)
1.01
" Assessment of pharmacodynamic response onset and reversibility kinetics indicated that approximately 7 days of dosing were required to achieve maximal responses, which persisted for at least 2 days after cessation of dosing."( Non-clinical Pharmacology of YTX-7739: a Clinical Stage Stearoyl-CoA Desaturase Inhibitor Being Developed for Parkinson's Disease.
Chang, B; Chung, CY; Le Bourdonnec, B; Lucas, M; Rhodes, KJ; Scannevin, RH; Tardiff, DF; Wrona, I, 2022
)
0.72
" Here, we developed an isogenic SNCA gene dosage model using CRISPR/Cas9 gene editing to introduce frameshift mutations into exon 2 of the SNCA coding region in human induced pluripotent stem cells (iPSCs) from a patient with an SNCA triplication."( Isogenic human SNCA gene dosage induced pluripotent stem cells to model Parkinson's disease.
Alejandra Morato Torres, C; Nallur Srinivasaraghavan, V; Schüle, B; Yang Chen, M; Zafar, F, 2022
)
0.72
" Overall, these findings suggest the ENS retains PFF dosage absent acute loss in function, however, does experience changes in growth cone morphology and dopamine-stimulated activity."( Aggregation of alpha-synuclein in enteric neurons does not impact function in vitro.
Bindas, AJ; Brady, R; Koppes, AN; Koppes, RA; Nichols, KN; Roth, NJ, 2022
)
1.07
[information is derived through text-mining from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Research

Studies (10,687)

TimeframeStudies, This Drug (%)All Drugs %
pre-19900 (0.00)18.7374
1990's122 (1.14)18.2507
2000's2177 (20.37)29.6817
2010's5350 (50.06)24.3611
2020's3038 (28.43)2.80
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Market Indicators

Research Demand Index: 84.07

According to the monthly volume, diversity, and competition of internet searches for this compound, as well the volume and growth of publications, there is estimated to be very strong demand-to-supply ratio for research on this compound.

MetricThis Compound (vs All)
Research Demand Index84.07 (24.57)
Research Supply Index9.29 (2.92)
Research Growth Index5.64 (4.65)
Search Engine Demand Index153.94 (26.88)
Search Engine Supply Index2.00 (0.95)

This Compound (84.07)

All Compounds (24.57)

Study Types

Publication TypeThis drug (%)All Drugs (%)
Trials29 (0.27%)5.53%
Reviews1,902 (17.58%)6.00%
Case Studies189 (1.75%)4.05%
Observational13 (0.12%)0.25%
Other8,688 (80.29%)84.16%
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]