Alpha-synuclein aggregation induced by brief ischemia negatively impacts neuronal survival in vivo: a study in [A30P]alpha-synuclein transgenic mouse.
Alpha-synuclein oligomerization and aggregation are considered to have a role in the pathogenesis of neurodegenerative diseases. However, despite numerous in vitro studies, the impact of aggregates in the intact brain is unclear. In vitro, oxidative/nitrative stress and acidity induce α-synuclein oligomerization. These conditions favoring α-synuclein fibrillization are present in the ischemic brain, which may serve as an in vivo model to study α-synuclein aggregation. In this study, we show that 30-minute proximal middle cerebral artery (MCA) occlusion and 72 hours reperfusion induce oligomerization of wild-type α-synuclein in the ischemic mouse brain. The nonamyloidogenic isoform β-synuclein did not form oligomers. Alpha-synuclein aggregates were confined to neurons and colocalized with ubiquitin immunoreactivity. We also found that 30 minutes proximal MCA occlusion and 24 hours reperfusion induced larger infarcts in C57BL/6(Thy1)-h[A30P]alphaSYN transgenic mice, which have an increased tendency to form synuclein fibrils. Trangenics also developed more selective neuronal necrosis when subjected to 20 minutes distal MCA occlusion and 72 hours reperfusion. Enhanced 3-nitrotyrosine immunoreactivity in transgenic mice suggests that oxidative/nitrative stress may be one of the mechanisms mediating aggregate toxicity. Thus, the increased vulnerability of transgenic mice to ischemia suggests that α-synuclein aggregates not only form during ischemia but also negatively impact neuronal survival, supporting the idea that α-synuclein misfolding may be neurotoxic.
Unal-Cevik
Isin
I
Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
Gursoy-Ozdemir
Yasemin
Y
Yemisci
Muge
M
Lule
Sevda
S
Gurer
Gunfer
G
Can
Alp
A
Müller
Veronica
V
Kahle
Philip J
PJ
Dalkara
Turgay
T
D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D002470:Cell Survival; D004198:Disease Susceptibility; D004351:Drug Resistance; D019286:Endopeptidase K / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons; D014018:Tissue Distribution; D025801:Ubiquitin / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D025801:Ubiquitin; D051844:alpha-Synuclein; D019286:Endopeptidase K