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

被引：57

作者：

Hasegawa, Takafumi ^{[1
]}

Baba, Toru ^{[1
]}

Kobayashi, Michiko ^{[1
]}

Konno, Masatoshi ^{[1
]}

Sugeno, Naoto ^{[1
]}

Kikuchi, Akio ^{[1
]}

Itoyama, Yasuto ^{[1
,2
]}

Takeda, Atsushi ^{[1
]}

机构：

[1] Tohoku Univ, Sch Med, Dept Neurol, Aoba Ku, Sendai, Miyagi 9808574, Japan

[2] Natl Ctr Neurol & Psychiat, Natl Ctr Hosp Mental Nervous & Muscular Disorders, Kodaira, Tokyo 1878502, Japan

来源：

NEUROCHEMISTRY INTERNATIONAL | 2010年 / 57卷 / 08期

关键词：

Multiple system atrophy; Tubulin polymerization promoting protein; alpha Synuclein; Glial cytoplasmic inclusion; Oligodendroglia; Sirtuin; 2; GLIAL CYTOPLASMIC INCLUSIONS; PARKINSONS-DISEASE; PROTEIN TPPP/P25; MOUSE MODEL; PHOSPHORYLATION; AGGREGATION; TUBULIN; DEATH; ACCUMULATION; EXPRESSION;

D O I：

10.1016/j.neuint.2010.09.002

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder presenting variable combinations of parkinsonism cerebellar ataxia corticospinal and autonomic dysfunction Alpha-synuclein (alpha-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 alpha-SYN aggregation To gain insight Into the molecular pathomechanisms of GCI formation and subsequent oligodendroglial degeneration we ectopically expressed alpha-SYN and TPPP in HEK293T and oligodendroglial KG1C cell lines Here we showed that TPPP specifically accelerated alpha-SYN oligomer formation and co-immunoprecipitation analysis revealed the specific interaction of TPPP and alpha-SYN Moreover phosphorylation of alpha-SYN at Ser-129 facilitated the TPPP-mediated alpha-SYN oligomerization TPPP facilitated alpha-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 (C) 2010 Published by Elsevier Ltd

引用

页码：857 / 866

页数：10

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