alpha-synuclein and Stroke

Post-stroke secondary brain damage is significantly influenced by the induction and accumulation of α-Synuclein (α-Syn). α-Syn-positive inclusions are often present in tauopathies and elevated tau levels and phosphorylation promotes neurodegeneration. Glycogen synthase kinase 3β (GSK-3β) is a known promoter of tau phosphorylation. We currently evaluated the interaction of α-Syn with GSK-3β and tau in post-ischemic mouse brain. Transient focal ischemia led to increased cerebral protein-protein interaction of α-Syn with both GSK-3β and tau and elevated tau phosphorylation. Treatment with a GSK-3β inhibitor prevented post-ischemic tau phosphorylation. Furthermore, α-Syn interaction was observed to be crucial for post-ischemic GSK-3β-dependent tau hyperphosphorylation as it was not seen in α-Syn knockout mice. Moreover, tau knockout mice show significantly smaller brain damage after transient focal ischemia. Overall, the present study indicates that GSK-3β catalyzes the α-Syn-dependent tau phosphorylation and preventing this interaction is crucial to limit post-ischemic secondary brain damage.

Topics: alpha-Synuclein; Animals; Brain; Brain Injuries; Glycogen Synthase Kinase 3 beta; Mice; Mice, Knockout; Phosphorylation; Stroke; tau Proteins

Atrial fibrillation (AF) is the most common type of persistent arrhythmia. Although its incidence has been increasing, the pathogenesis of AF in stroke remains unclear. In this study, a total of 30 participants were recruited, including 10 controls, 10 patients with AF and 10 patients with AF and stroke (AF + STROKE). Differentially expressed genes (DEGs) were identified, and functional annotation of DEGs, comparative toxicogenomic database analysis associated with cardiovascular diseases, and predictions of miRNAs of hub genes were performed. Using RT-qPCR, biological process and support vector machine neural networks, numerous DEGs were found to be related to AF. HBG1, SNCA and GYPB were found to be upregulated in the AF group. Higher expression of hub genes in AF and AF + STROKE groups was detected via RT-PCR. Upon training the biological process neural network of SNCA and GYPB for HBG1, only small differences were detected. Based on the support vector machine, the predicted value of SNCA and GYPB for HBG1 was 0.9893. Expression of the hub genes of HBG1, SNCA and GYPB might therefore be significantly correlated to AF. These genes are involved in the incidence of AF complicated by stroke, and may serve as targets for early diagnosis and treatment.

Topics: alpha-Synuclein; Atrial Fibrillation; Biomarkers; Gene Regulatory Networks; Glycophorins; Hemoglobins; Humans; Neural Networks, Computer; Stroke; Support Vector Machine

Topics: alpha-Synuclein; Animals; Brain; Brain Ischemia; Down-Regulation; Endosomes; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Models, Animal; Nedd4 Ubiquitin Protein Ligases; Neurodegenerative Diseases; Neurons; Neuroprotection; Parkinson Disease; Protein Aggregation, Pathological; Protein Processing, Post-Translational; Stroke; Ubiquitin-Protein Ligases; Ubiquitination; Up-Regulation

Topics: alpha-Synuclein; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Autism Spectrum Disorder; Bacterial Proteins; Clinical Trials as Topic; Depression; Female; Gastrointestinal Microbiome; Humans; Interleukin-17; Limosilactobacillus reuteri; Mice; Niacinamide; Parkinson Disease; Pregnancy; Stroke; Th17 Cells; Vagus Nerve

α-Synuclein is a soluble monomer abundant in the central nervous system. Aggregates of α-synuclein, consisting of higher-level oligomers and insoluble fibrils, have been observed in many chronic neurological diseases and are implicated in neurotoxicity and neurodegeneration. α-Synuclein has recently been shown to aggregate following acute ischemic stroke, exacerbating neuronal damage. Propofol is an intravenous anesthetic that is commonly used during intravascular embolectomy following acute ischemic stroke. While propofol has demonstrated neuroprotective properties following brain injury, the mechanism of protection in the setting of ischemic stroke is unclear. In this study, propofol administration significantly reduced the neurotoxic aggregation of α-synuclein, decreased the infarct area, and attenuated the neurological deficits after ischemic stroke in a mouse model. We then demonstrated that the propofol-induced reduction of α-synuclein aggregation was associated with increased mammalian target of rapamycin/ribosomal protein S6 kinase beta-1 signaling pathway activity and reduction of the excessive autophagy occurring after acute ischemic stroke.

Topics: alpha-Synuclein; Animals; Behavior, Animal; Brain Infarction; Brain Ischemia; Disease Models, Animal; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Propofol; Psychomotor Performance; Stroke

Increased expression of α-Syn (α-Synuclein) is known to mediate secondary brain damage after stroke. We presently studied if α-Syn knockdown can protect ischemic brain irrespective of sex and age.. Adult and aged male and female mice were subjected to transient middle cerebral artery occlusion. α-Syn small interfering RNA (siRNA) was administered intravenous at 30 minutes or 3 hour reperfusion. Poststroke motor deficits were evaluated between day 1 and 7 and infarct volume was measured at day 7 of reperfusion.. α-Syn knockdown significantly decreased poststroke brain damage and improved poststroke motor function recovery in adult and aged mice of both sexes. However, the window of therapeutic opportunity for α-Syn siRNA is very limited.. α-Syn plays a critical role in ischemic brain damage and preventing α-Syn protein expression early after stroke minimizes poststroke brain damage leading to better functional outcomes irrespective of age and sex.

Topics: Age Factors; alpha-Synuclein; Animals; Brain; Disease Models, Animal; Female; Gene Knockdown Techniques; Infarction, Middle Cerebral Artery; Male; Mice; Recovery of Function; RNA, Small Interfering; Sex Factors; Stroke

Numerous clinical studies have documented the high incidence of cognitive impairment after stroke. However, there is only limited knowledge about the underlying mechanisms. Interestingly, there is emerging evidence suggesting that cognitive function after stroke may be affected due to reduced waste clearance and subsequent accumulation of neurotoxic proteins. To further explore this potential association, we utilised a model of experimental stroke in mice. Specifically, a photothrombotic vascular occlusion targeting motor and sensory parts of the cerebral cortex was induced in young adult mice, and changes in cognition were assessed using a touchscreen platform for pairwise visual discrimination. The results showed that the execution of the visual discrimination task was impaired in mice 10 to 14 days post-stroke compared to sham. Stroke also induced significant neuronal loss within the peri-infarct, thalamus and the CA1 sub-region of the hippocampus. Further, immunohistochemical and protein analyses of the selected brain regions revealed an increased accumulation and aggregation of both amyloid-β and α-synuclein. These alterations were associated with significant disturbances in the aquaporin-4 protein expression and polarization at the astrocytic end-feet. The results suggest a link between the increased accumulation of neurotoxic proteins and the stroke-induced cognitive impairment. Given that the neurotoxic protein accumulation appeared alongside changes in astrocytic aquaporin-4 distribution, we suggest that the function of the waste clearance pathways in the brain post-stroke may represent a therapeutic target to improve brain recovery.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Animals; Aquaporin 4; Astrocytes; Brain; Cognitive Dysfunction; Male; Mice; Mice, Inbred C57BL; Stroke; Vision Disorders; Visual Perception

Ischemic stroke, which is caused by a clot that blocks blood flow to the brain, can be severely disabling and sometimes fatal. We previously showed that transient focal ischemia in a rat model induces extensive temporal changes in the expression of cerebral microRNAs, with a sustained decrease in the abundance of miR-7a-5p (miR-7). Here, we evaluated the therapeutic efficacy of a miR-7 mimic oligonucleotide after cerebral ischemia in rodents according to the Stroke Treatment Academic Industry Roundtable (STAIR) criteria. Rodents were injected locally or systemically with miR-7 mimic before or after transient middle cerebral artery occlusion. Decreased miR-7 expression was observed in both young and aged rats of both sexes after cerebral ischemia. Pre- or postischemic treatment with miR-7 mimic decreased the lesion volume in both sexes and ages studied. Furthermore, systemic injection of miR-7 mimic into mice at 30 min (but not 2 hours) after cerebral ischemia substantially decreased the lesion volume and improved motor and cognitive functional recovery with minimal peripheral toxicity. The miR-7 mimic treatment substantially reduced the postischemic induction of α-synuclein (α-Syn), a protein that induces mitochondrial fragmentation, oxidative stress, and autophagy that promote neuronal cell death. Deletion of the gene encoding α-Syn abolished miR-7 mimic-dependent neuroprotection and functional recovery in young male mice. Further analysis confirmed that the transcript encoding α-Syn was bound and repressed by miR-7. Our findings suggest that miR-7 mimics may therapeutically minimize stroke-induced brain damage and disability.

Topics: Administration, Intravenous; alpha-Synuclein; Animals; Apoptosis; Autophagy; Brain Ischemia; Female; Male; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Mitochondrial Dynamics; Motor Skills Disorders; Oxidative Stress; Rats; Rats, Inbred SHR; Reperfusion Injury; Stroke

In the present study, we detected the level of oligomeric form of α-synuclein in the red blood cells of ischemic stroke, Parkinson's disease, and normal people and compared the differences to assess the diagnosis potential of α-synuclein in ischemic stroke patients. 86 ischemic stroke, 100 PD, and 102 healthy cases were enrolled in the present study. Total protein amount in the red blood cells were quantified by BCA assay using spectrophotometer. Levels of oligomeric form of α-synuclein were characterized by a sandwich ELISA. Analysis of correlation analysis and receiver operating characteristic curve were conducted. Significant differences were detected in the levels of oligomeric forms of α-synuclein in different samples' blood cells (P < 0.05); the levels of total protein in (188.1 ± 33.9 mmol/L) healthy people were significantly higher than that of PD (147.7 ± 45.0 mmol/L) and ischemic stroke groups (142.9 ± 43.0 mmol/L) (P < 0.05). There was no correlation between the age of patients and level of α-synuclein (R (2) = 0.216 in ischemic stroke group and -0.104 in PD group) and the receiver operating characteristic curve analysis showed a high sensitivity of α-synuclein in discriminating ischemic stroke (sensitivity was 63.7 % and specificity was 9.6 %) and PD (sensitivity was 44.1 % and specificity was 12.5 %) patients from the controls. The levels of oligomeric form of α-synuclein of red blood cells in ischemic stroke and Parkinson's disease patients were both significant higher than normal people. And the level of oligomeric form α-synuclein showed a potential for diagnosis of ischemic stroke in clinic.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Analysis of Variance; Brain Ischemia; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Parkinson Disease; ROC Curve; Stroke; Young Adult

α-Synuclein (α-Syn), one of the most abundant proteins in the CNS, is known to be a major player in the neurodegeneration observed in Parkinson's disease. We currently report that transient focal ischemia upregulates α-Syn protein expression and nuclear translocation in neurons of the adult rodent brain. We further show that knockdown or knock-out of α-Syn significantly decreases the infarction and promotes better neurological recovery in rodents subjected to focal ischemia. Furthermore, α-Syn knockdown significantly reduced postischemic induction of phospho-Drp1, 3-nitrotyrosine, cleaved caspase-3, and LC-3 II/I, indicating its role in modulating mitochondrial fragmentation, oxidative stress, apoptosis, and autophagy, which are known to mediate poststroke neuronal death. Transient focal ischemia also significantly upregulated serine-129 (S129) phosphorylation (pα-Syn) of α-Syn and nuclear translocation of pα-Syn. Furthermore, knock-out mice that lack PLK2 (the predominant kinase that mediates S129 phosphorylation) showed better functional recovery and smaller infarcts when subjected to transient focal ischemia, indicating a detrimental role of S129 phosphorylation of α-Syn. In conclusion, our studies indicate that α-Syn is a potential therapeutic target to minimize poststroke brain damage.. Abnormal aggregation of α-synuclein (α-Syn) has been known to cause Parkinson's disease and other chronic synucleinopathies. However, even though α-Syn is linked to pathophysiological mechanisms similar to those that produce acute neurodenegerative disorders, such as stroke, the role of α-Syn in such disorder is not clear. We presently studied whether α-Syn mediates poststroke brain damage and more importantly whether preventing α-Syn expression is neuroprotective and leads to better physiological and functional outcome after stroke. Our study indicates that α-Syn is a potential therapeutic target for stroke therapy.

Topics: alpha-Synuclein; Animals; Brain Infarction; Brain Ischemia; Caspase 3; Death-Associated Protein Kinases; Disease Models, Animal; Gene Expression Regulation; Male; Mice; Mice, Transgenic; Microtubule-Associated Proteins; Motor Activity; PC12 Cells; Protein Serine-Threonine Kinases; Rats; Rats, Inbred SHR; RNA, Small Interfering; Stroke; Tyrosine

The Na(+)-K(+)-2Cl(-) cotransporter localized in the brain vascular endothelium has been shown to be important in the evolution of cerebral edema following experimental stroke. Previous in vivo studies have demonstrated that bumetanide, a selective Na(+)-K(+)-2Cl(-) cotransport inhibitor, attenuates ischemia-evoked cerebral edema. Recently, bumetanide has been shown to also inhibit water permeability via aquaporin-4 (AQP4) expressed in Xenopus laevis oocytes. We tested the hypothesis that the perivascular pool of AQP4 plays a significant role in the anti-edema effect of bumetanide by utilizing wild-type (WT) mice as well as mice with targeted disruption of alpha-syntrophin (alpha-Syn(-/-)) that lack the perivascular pool of AQP4.. Isoflurane-anesthetized adult male WT C57Bl6 and alpha-Syn(-/-) mice were subjected to 90 min middle cerebral artery occlusion (MCAO) followed by 24 or 48 h of reperfusion. Adequacy of MCAO and reperfusion was monitored with laser-Doppler flowmetry over the ipsilateral parietal cortex. Infarct volume (tetrazolium staining), cerebral edema (wet-to-dry ratios), and AQP4 protein expression (immunoblotting) were determined in different treatment groups in separate sets of experiments.. Bumetanide significantly attenuated infarct volume and decreased ipsilateral hemispheric water content in WT mice compared to vehicle treatment. In alpha-Syn(-/-) mice, bumetanide treatment had no effect on infarct volume or ischemia-evoked cerebral edema. Bumetanide-treated WT mice had a significant attenuation of AQP4 protein expression at 48 h post-MCAO compared to vehicle-treated WT mice.. These data suggest that bumetanide exerts its neuroprotective and anti-edema effects partly via blockade of the perivascular pool of AQP4 and may have therapeutic potential for ischemic stroke in the clinical setting.

Topics: alpha-Synuclein; Animals; Aquaporin 4; Brain Edema; Bumetanide; Cerebral Infarction; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroprotective Agents; Sodium Potassium Chloride Symporter Inhibitors; Stroke