alpha-synuclein and Essential-Tremor

Molecular chaperones and co-chaperones facilitate the assembly of newly synthesized polypeptides and refolding of unfolded or misfolded proteins, thereby maintaining protein homeostasis in cells. As co-chaperones of the master chaperone heat shock protein (HSP) 70, the HSP40 (DNAJ) proteins are largest chaperone family in eukaryotic cells. They contain a characteristic J-domain which mediates interaction with HSP70, thereby helping protein folding. It is well perceived that protein homeostasis is vital for neuronal health. DNAJ family proteins have been linked to the occurrence and progression of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia, Charcot-Marie-Tooth disease, spinal muscular atrophy, distal hereditary motor neuropathy, limb-girdle type muscular dystrophy, neuronal ceroid lipofuscinosis and essential tremor in recent studies. DNAJA1 effectively degrades huntington aggregates; DNAJB1 can degrade protein aggregates ataxin-3; DNAJB2 can inhibit the formation of huntington aggregates; DNAJB6 can inhibit the aggregation of Aβ

Topics: alpha-Synuclein; Essential Tremor; HSP40 Heat-Shock Proteins; Humans; Molecular Chaperones; Nerve Tissue Proteins; Neurodegenerative Diseases; Protein Folding

Given the overlap between Parkinson's disease and essential tremor, we examined genetic variants in α-synuclein (SNCA) as risk determinants for essential tremor.. Samples from 661 essential tremor subjects and 1316 control subjects from 4 participating North American sites were included in this study. Parkinson's disease samples (n = 427) were compared against controls. Twenty variants were selected for association analysis within the SNCA locus. Individual logistic regression analyses against essential tremor diagnosis were run for each variant and then combined using meta-analysis.. Our results do not show a significant association between variants in the SNCA locus and risk of essential tremor, whereas the established association of SNCA variants with Parkinson's disease risk was observed.. Whereas genetic factors are likely to play a large role in essential tremor pathogenesis, our results do not support a role for common SNCA genetic variants in risk for essential tremor.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; alpha-Synuclein; Essential Tremor; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Male; Middle Aged; Parkinson Disease; Risk Factors; Young Adult

Parkinson's disease (PD) was noted to have a familial component as early as 1880 (Leroux, 1880). More recently, the discovery of several genetic factors influencing parkinsonism has emphasized the importance of heredity in PD. The clinical spectrum of familial parkinsonism is wide; it includes not only PD, but also dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), essential tremor, and other disorders. In the general population, it is likely that PD results from combined genetic and environmental factors, most of which are not yet known. The discovery of causal mutations in the gene for alpha-synuclein, parkin, and of genetic linkages to chromosomes 2p4, 4p5, and three loci on 1q6-8 have revolutionized PD research. This review focuses on recent progress in the Mendelian genetics of PD and those diseases in which parkinsonism is a prominent feature, and considers how these discoveries modify our beliefs regarding the etiology and pathogenesis of these disorders.

Topics: alpha-Synuclein; Chromosome Mapping; Essential Tremor; Humans; Lewy Body Disease; Ligases; Nerve Tissue Proteins; Parkinson Disease; Parkinsonian Disorders; Supranuclear Palsy, Progressive; Synucleins; Ubiquitin-Protein Ligases

Parkinson's disease (PD) and essential tremor (ET) are two common adult-onset tremor disorders in which prevalence increases with age. PD is a neurodegenerative condition with progressive disability. In ET, neurodegeneration is not an established etiology. We sought to determine whether an underlying metabolic pattern may differentiate ET from PD. Circulating metabolites in plasma and cerebrospinal fluid (CSF) were analyzed using gas chromatography-mass spectroscopy. There were several disrupted pathways in PD compared to ET plasma including glycolysis, tyrosine, phenylalanine, tyrosine biosynthesis, purine and glutathione metabolism. Elevated α-synuclein levels in plasma and CSF distinguished PD from ET. The perturbed metabolic state in PD was associated with imbalance in the pentose phosphate pathway, deficits in energy production, and change in NADPH, NADH and nicotinamide phosphoribosyltransferase levels. This work demonstrates significant metabolic differences in plasma and CSF of PD and ET patients.

Topics: Aged; alpha-Synuclein; Biomarkers; Diagnosis, Differential; Essential Tremor; Female; Humans; Male; Middle Aged; NAD; Nicotinamide Phosphoribosyltransferase; Parkinson Disease; Pentose Phosphate Pathway

The Essential Tremor Centralized Brain Repository is the largest repository of prospectively collected essential tremor (ET) brains (n = 231). Hence, we are uniquely poised to address several questions: What proportion of ET cases has Lewy pathology (LP)? What is the nature of that pathology and how does it relate to other comorbidities? Each brain had a complete neuropathological assessment, including α-synuclein immunostaining. We created a 10-category classification scheme to fully encapsulate the patterns of LP observed. Four metrics of cerebellar pathology were also quantified. Mean age at death = 89.0 ± 6.4 years. Fifty-eight (25.1%) had LP and 46 (19.9%) had early to late stages of Parkinson disease (PD). LP was very heterogeneous. Of 58 cases with LP, 14 (24.1%) clinically developed possible PD or PD after a latency of 5 or more years. There was a similar degree of cerebellar pathology in ET cases both with and without LP. In summary, 1 in 4 ET cases had LP-a proportion that seems higher than expected based on studies among control populations. Heterogeneous LP likely reflects clinical associations between ET and PD, and ET with Alzheimer disease-type neuropathology. These data further our understanding of ET and its relatedness to other degenerative diseases.

Topics: alpha-Synuclein; Brain; Essential Tremor; Humans; Lewy Bodies; Parkinson Disease

Studies have revealed controversial results regarding the diagnostic accuracy of plasma α-synuclein levels in patients with Parkinson's disease (PD). This study was aimed to analyze the diagnostic accuracy of plasma α-synuclein in PD versus healthy controls and patients with essential tremor (ET).. In this cross-sectional study, we included de novo (n = 19) and advanced PD patients [OFF (n = 33), and On (n = 35) states], patients with ET (n = 19), and controls (n = 35). The total plasma α-synuclein levels were determined using an ELISA sandwich method. We performed adjusted multivariate regression analysis to estimate the association of α-synuclein levels with group conditions [controls, ET, and de novo, OFF and ON-PD]. We studied the diagnostic accuracy of plasma α-synuclein using the area under the curve (AUC).. The plasma α-synuclein levels were higher in controls compared to PD and ET (p < 0.0001), discriminating de novo PD from controls (AUC = 0.74, 95% CI 0.60-0.89), with a trend towards in advanced PD (OFF state) from ET (AUC = 0.69, 95% CI 0.53-0.84).. This is the first study examining and comparing plasma α-synuclein levels in ET vs. PD and controls. Preliminary findings suggest that plasma α-synuclein levels might help to discriminate de novo and advanced PD from controls and ET.

Topics: alpha-Synuclein; Biomarkers; Cross-Sectional Studies; Essential Tremor; Humans; Parkinson Disease

Parkinson's disease (PD) is a common movement disorder. Alpha-synuclein (α-synuclein) plays a critical role in PD. In this study, we evaluated the level of central nervous system (CNS)-derived exosomal α-synuclein in serum, which may be regarded as a specific peripheral biomarker for PD. We recruited patients with PD in the early stage along with essential tremor (ET), and we recruited age- and gender-matched healthy subjects as healthy controls (HC). We divided patients with PD into the tremor-dominant (TD) group and the non-tremor-dominant (NTD) group. We evaluated the levels of α-synuclein in CNS-derived exosomes in serum samples. As a result, there was a significant difference between four groups (p<0.05). This level was lower in the PD group than in the ET and HC groups (p<0.05). Among the PD group, this level was lower in the NTD group than in the TD group (p<0.05). Furthermore, the performance of serum CNS-derived exosomal α-synuclein was found to moderately aid in PD diagnosis (AUC=0.675, p<0.05) and had a potential to diagnose NTD (AUC=0.761, p<0.05). Therefore, CNS-derived exosomal α-synuclein in the serum may be regarded as a biomarker to identify PD from ET and HC in the early stage. It may also be used to identify different motor types in PD. The pathogenesis of PD in different motor types may be different, which needs further research.

Topics: alpha-Synuclein; Biomarkers; Central Nervous System; Cohort Studies; Essential Tremor; Exosomes; Female; Humans; Male; Middle Aged; Neural Cell Adhesion Molecule L1; Parkinson Disease; Sensitivity and Specificity

Although the number of postmortem studies in essential tremor (ET) has grown in recent years, clinical-pathological correlations remain limited. We are unaware of a study that has assessed whether the pathological changes in ET, if asymmetric, lateralize to the cerebellar hemisphere that is ipsilateral to the arm with more severe action tremor, as one would predict if the lesions were tremor producing. We compared postmortem changes in the right vs. left cerebellar hemispheres in ET and examined how these correlated with asymmetry of tremor on neurological examination. Action tremor in each arm was quantified using a reliable and valid clinical rating scale. Cases were divided into three clinical groups: tremor more severe on right, tremor more severe on left, and tremor symmetric. Calbindin D28k immunohistochemistry was performed on 100 μm vibrotome sections from a standard tissue block of both right and left neocerebellums to quantify Purkinje cell linear density, torpedo counts, and a group of previously described changes in Purkinje cell axonal shape (thickened axonal profiles) and connectivity (axon recurrent collaterals, axonal branching, terminal axonal sprouting, arciform axons, extent of recurrent collateral plexus). ET cases were divided into three postmortem groups: findings greatest on right, findings greatest on left, and findings symmetric. In 18 (72.0 %) of 25 ET cases, clinical and pathological features were concordant (i.e., both clinically and pathologically right-predominant (one case), both clinically and pathologically left-predominant (five cases), or both clinically and pathologically symmetric (12 cases), p = 0.007). In the remaining seven (28.0 %) ET cases, clinical and pathological data were not concordant, and in none were they completely discordant (i.e., tremor was more severe on the right, and postmortem cerebellar changes were paradoxically more severe on the left or vice versa). Among the seven ET cases with >20 % side-to-side difference in tremor severity, six cases (85.7 %) had the expected pathological asymmetry, with quantified postmortem cerebellar changes more marked ipsilateral to the more clinically affected side. We also created continuous measures of asymmetry. For the entire sample, there was a positive correlation between the clinical asymmetry index and the pathological asymmetry index = 0.52, p = 0.01 (i.e., the right-left difference in clinical asymmetry was correlated with the right-left difference in postmo

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Autopsy; Calbindin 1; Cerebellum; Essential Tremor; Female; Functional Laterality; Humans; Linear Models; Male; Middle Aged; Purkinje Cells; Severity of Illness Index; Young Adult

Rest tremor may occur in as many as 30% of essential tremor (ET) patients. It is not clear whether this tremor is a sentinel marker for brainstem Lewy body pathology. Here we report the clinical and post-mortem findings of nine ET cases with upper-extremity rest tremor in the absence of other parkinsonian features.. All brains had a complete neuropathological assessment. Tissue sections from the brainstem and basal ganglia were immunostained with α-synuclein antibody.. All cases had longstanding ET (median duration=42 years) with moderate to severe arm tremor. Rest tremor involved both arms in seven (77.8%) cases and one arm in two cases. The rest tremor score was correlated with the total action tremor score (r=0.69, p=0.04). The number of torpedoes was elevated, and Purkinje cells, reduced. Post-mortem changes in the substantia nigra pars compacta (SNc), caudate, putamen and globus pallidum were minimal, and neither Lewy bodies nor Lewy neurites were evident.. In nine ET brains with upper-extremity rest tremor, neither Lewy body-containing neurons nor Lewy neurites were found on α-synuclein immunostained sections, and other pathological changes in the basal ganglia were minimal. These data support the notion that isolated rest tremor in longstanding ET is not the expression of underlying Lewy body pathology in the SNc.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Basal Ganglia; Brain Stem; Caudate Nucleus; Essential Tremor; Female; Globus Pallidus; Humans; Lewy Bodies; Male; Middle Aged; Purkinje Cells; Putamen; Severity of Illness Index; Substantia Nigra; Tremor

Previous epidemiologic and genetic studies have suggested a link between Parkinson disease (PD), essential tremor (ET), and restless legs syndrome (RLS).. We describe the clinical, PET, and pathologic characteristics of an extensive kindred from Arkansas with hereditary PD, ET, and RLS. The pedigree contains 138 individuals. Sixty-five family members were examined neurologically up to 3 times from 2004 to 2010. Clinical data were collected from medical records and questionnaires. Genetic studies were performed. Five family members underwent multitracer PET. Two individuals with PD were examined postmortem.. Eleven family members had PD with generally mild and slowly progressive symptoms. Age at onset was between 39 and 74 years (mean 59.1, SD 13.4). All individuals treated with l-dopa responded positively. Postural or action tremor was present in 6 individuals with PD, and in 19 additional family members. Fifteen persons reported symptoms of RLS. PET showed reduced presynaptic dopamine function typical of sporadic PD in a patient with PD and ET, but not in persons with ET or RLS. The inheritance pattern was autosomal dominant for PD and RLS. No known pathogenic mutation in PD-related genes was found. Fourteen of the family members with PD, ET, or RLS had depression. Neuropathologic examination revealed pallidonigral pigment spheroid degeneration with ubiquitin-positive axonal spheroids, TDP43-positive pathology in the basal ganglia, hippocampus, and brainstem, and only sparse Lewy bodies.. Familial forms of PD, ET, RLS, and depression occur in this family. The genetic cause remains to be elucidated.

Topics: Adult; Aged; alpha-Synuclein; Brain; Depression; DNA-Binding Proteins; Dynactin Complex; Essential Tremor; Eukaryotic Initiation Factor-4G; Family Health; Female; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Longitudinal Studies; Male; Mental Status Schedule; Microtubule-Associated Proteins; Middle Aged; Parkinsonian Disorders; Positron-Emission Tomography; Protein Serine-Threonine Kinases; Restless Legs Syndrome

A specific allele of the NACP-Rep1 polymorphism within the alpha-synuclein promoter was found to be associated both with Parkinson's disease and essential tremor. We repeated the association study on a large series of Italian patients with essential tremor using a panel of polymorphisms within the alpha-synuclein gene. Our results did not confirm the association reported previously and failed to identify a alpha-synuclein specific haplotype as susceptibility factor for essential tremor.

Topics: Aged; Alleles; alpha-Synuclein; Essential Tremor; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Italy; Male; Middle Aged; Nerve Tissue Proteins; Parkinson Disease; Polymorphism, Genetic; Promoter Regions, Genetic; Synucleins

Missense mutations of the alpha-synuclein gene have been reported to explain a few kindreds with autosomal dominant Parkinson's disease (PD). In order to identify mutations in our PD patients, we have screened the coding region and 5'flanking region of the gene. DNA samples from 50 patients with familial PD were screened via single-strand conformation polymorphism (SSCP) for mutations in the alpha-synuclein gene. The 5' flanking region was examined in 117 additional PD patients (27 patients with unclear family history for PD, and 90 patients without family history) and in 169 control subjects. We found one change (G199A) in exon 4 in one family with a pattern of autosomal dominant PD. However, this mutation did not result in an amino acid substitution (valine) and did not segregate completely with PD. The analysis of the 5' flanking region also showed a new polymorphism, a nucleotide insertion (- 164insA) linked to a nucleotide substitution (C-116G), in patients and in controls. The -164insA/C-116G allele was present in 52.3% of the patients and in 47.6% of the controls. We did not find significant differences regarding the allelic and genotype frequencies between PD and control groups. These results suggest that mutations in the alpha-synuclein gene are a very rare cause of familial PD and that the novel -164insA/C-116G polymorphism in the 5' flanking region does not confer susceptibility to develop PD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Base Pair Mismatch; Case-Control Studies; Cytosine; Essential Tremor; Female; Gene Expression Regulation; Genetic Predisposition to Disease; Genotype; Guanine; Humans; Male; Middle Aged; Mutation; Nerve Tissue Proteins; Parkinson Disease; Pedigree; Phosphoproteins; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Spain; Synucleins