Role of TPPP/p25 on α-synuclein-mediated oligodendroglial degeneration and the protective effect of SIRT2 inhibition in a cellular model of multiple system atrophy

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• 作者：Takafumi Hasegawa ; Toru Baba ; Michiko Kobayashi ; Masatoshi Konno ; Naoto Sugeno ; Akio Kikuchi ; Yasuto Itoyama ; Atsushi Takeda
• 关键词：Multiple system atrophy ; Tubulin polymerization promoting protein ; α ; -Synuclein ; Glial cytoplasmic inclusion ; Oligodendroglia ; Sirtuin 2
• 刊名：Neurochemistry International
• 出版年：2010
• 出版时间：December 2010
• 年：2010
• 卷：57
• 期：8
• 页码：857-866
• 全文大小：868 K

文摘

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder presenting variable combinations of parkinsonism, cerebellar ataxia, corticospinal and autonomic dysfunction. Alpha-synuclein (α-SYN)-immunopositive glial cytoplasmic inclusions (GCIs) represent the neuropathological hallmark of MSA, and tubulin polymerization promoting protein (TPPP)/p25 in oligodendroglia has been known as a potent stimulator of α-SYN aggregation. To gain insight into the molecular pathomechanisms of GCI formation and subsequent oligodendroglial degeneration, we ectopically expressed α-SYN and TPPP in HEK293T and oligodendroglial KG1C cell lines. Here we showed that TPPP specifically accelerated α-SYN oligomer formation and co-immunoprecipitation analysis revealed the specific interaction of TPPP and α-SYN. Moreover, phosphorylation of α-SYN at Ser-129 facilitated the TPPP-mediated α-SYN oligomerization. TPPP facilitated α-SYN-positive cytoplasmic perinuclear inclusions mimicking GCI in both cell lines; however, apoptotic cell death was only observed in KG1C cells. This apoptotic cell death was partly rescued by sirtuin 2 (SIRT2) inhibition. Together, our results provide further insight into the molecular pathogenesis of MSA and potential therapeutic approaches.