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.
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.
Hasegawa
Takafumi
T
Department of Neurology, Tohoku University School of Medicine, 1-1, Seiryomachi, Aobaku, Sendai, Miyagi 980-8574, Japan. hasegawa@neurol.med.tohoku.ac.jp
Baba
Toru
T
Kobayashi
Michiko
M
Konno
Masatoshi
M
Sugeno
Naoto
N
Kikuchi
Akio
A
Itoyama
Yasuto
Y
Takeda
Atsushi
A
D017209:Apoptosis / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D057809:HEK293 Cells; D006801:Humans; D019578:Multiple System Atrophy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009836:Oligodendroglia / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation / Q000502:physiology; D012694:Serine / Q000737:chemistry / Q000378:metabolism; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051844:alpha-Synuclein / Q000502:physiology*
D009419:Nerve Tissue Proteins; C118136:TPPP protein, human; D051844:alpha-Synuclein; D012694:Serine; D038362:Glycogen Synthase Kinase 3; C474199:SIRT2 protein, human; D056565:Sirtuin 2