title: Poststroke Induction of α-Synuclein Mediates Ischemic Brain Damage.
abstract: 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.
authors.affiliation: Department of Neurological Surgery, Neuroscience Training Program.
authors.forename: TaeHee
authors.identifier: 0000-0002-1980-7774
authors.initials: T
authors.lastname: Kim
authors.affiliation: Department of Neurological Surgery.
authors.forename: Suresh L
authors.initials: SL
authors.lastname: Mehta
authors.affiliation: Department of Neurological Surgery.
authors.forename: Balarama
authors.initials: B
authors.lastname: Kaimal
authors.affiliation: Department of Neurological Surgery.
authors.forename: Kirsten
authors.identifier: 0000-0002-9013-0946
authors.initials: K
authors.lastname: Lyons
authors.affiliation: Department of Neurological Surgery, Neuroscience Training Program, William S. Middleton Veterans Administration Hospital, Madison, Wisconsin 53705.
authors.forename: Robert J
authors.identifier: 0000-0002-1636-5456
authors.initials: RJ
authors.lastname: Dempsey
authors.affiliation: Department of Neurological Surgery, Neuroscience Training Program, Cellular & Molecular Pathology Graduate Program, University of Wisconsin, Madison, Wisconsin 53792 and William S. Middleton Veterans Administration Hospital, Madison, Wisconsin 53705 vemuganti@neurosurgery.wisc.edu.
authors.forename: Raghu
authors.initials: R
authors.lastname: Vemuganti
mesh_terms: D000818:Animals; D020520:Brain Infarction / Q000209:etiology; D002545:Brain Ischemia / Q000150:complications*; D053148:Caspase 3 / Q000378:metabolism; D064550:Death-Associated Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity / Q000502:physiology; D016716:PC12 Cells; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D051844:alpha-Synuclein; C002744:3-nitrotyrosine; D014443:Tyrosine; D064550:Death-Associated Protein Kinases; D017346:Protein Serine-Threonine Kinases; C444640:serum-inducible kinase; D053148:Caspase 3
keywords: brain; neuroprotection; stroke; α-synuclein