Journal
JOURNAL OF NEUROSCIENCE
Volume 36, Issue 26, Pages 7055-7065Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1241-16.2016
Keywords
alpha-synuclein; brain; neuroprotection; stroke
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Funding
- U.S. Department of Veterans Affairs Merit Review Grant [I01 BX002985]
- American Heart Association [15IRG23050015]
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alpha-Synuclein (alpha-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 alpha-Syn protein expression and nuclear translocation in neurons of the adult rodent brain. We further show that knockdown or knock-out of alpha-Syn significantly decreases the infarction and promotes better neurological recovery in rodents subjected to focal ischemia. Furthermore, alpha-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 (p alpha-Syn) of alpha-Syn and nuclear translocation of p alpha-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 p alpha-Syn. In conclusion, our studies indicate that alpha-Syn is a potential therapeutic target to minimize poststroke brain damage.
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