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
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收藏
页码：857 / 866
页数：10
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