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

Takafumi Hasegawa, Toru Baba, Michiko Kobayashi, Masatoshi Konno, Naoto Sugeno, Akio Kikuchi, Yasuto Itoyama, Atsushi Takeda

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)857-866
Number of pages10
JournalNeurochemistry International
Volume57
Issue number8
DOIs
Publication statusPublished - 2010 Dec

Keywords

  • Glial cytoplasmic inclusion
  • Multiple system atrophy
  • Oligodendroglia
  • Sirtuin 2
  • Tubulin polymerization promoting protein
  • α-Synuclein

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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