Association of the cytoskeletal GTP-binding protein Sept4/H5 with cytoplasmic inclusions found in Parkinson's disease and other synucleinopathies.
alpha-Synuclein-positive cytoplasmic inclusions are a pathological hallmark of several neurodegenerative disorders including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Here we report that Sept4, a member of the septin protein family, is consistently found in these inclusions, whereas five other septins (Sept2, Sept5, Sept6, Sept7, and Sept8) are not found in these inclusions. Sept4 and alpha-synuclein can also be co-immunoprecipitated from normal human brain lysates. When co-expressed in cultured cells, FLAG-tagged Sept4 and Myc-tagged alpha-synuclein formed detergent-insoluble complex, and upon treatment with a proteasome inhibitor, they formed Lewy body-like cytoplasmic inclusions. The tagged Sept4 and alpha-synuclein synergistically accelerated cell death induced by the proteasome inhibitor, and this effect was further enhanced by expression of another Lewy body-associated protein, synphilin-1, tagged with the V5 epitope. Moreover, co-expression of the three proteins (tagged Sept4, alpha-synuclein, and synphilin-1) was sufficient to induce cell death. These data raise the possibility that Sept4 is involved in the formation of cytoplasmic inclusions as well as induction of cell death in alpha-synuclein-associated neurodegenerative disorders.
Ihara
Masafumi
M
Department of Neurology, Kyoto University Graduate School of Medicine, Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. ihara@kuhp.kyoto-u.ac.jp
Tomimoto
Hidekazu
H
Kitayama
Hitoshi
H
Morioka
Yoko
Y
Akiguchi
Ichiro
I
Shibasaki
Hiroshi
H
Noda
Makoto
M
Kinoshita
Makoto
M
D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism* / Q000502:physiology; D001921:Brain / Q000473:pathology; D002352:Carrier Proteins / Q000502:physiology; D016923:Cell Death; D002460:Cell Line; D003598:Cytoskeletal Proteins; D003599:Cytoskeleton / Q000737:chemistry; D020558:GTP Phosphohydrolases / Q000378:metabolism* / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry*; D047908:Intracellular Signaling Peptides and Proteins; D016631:Lewy Bodies / Q000737:chemistry; D051379:Mice; D009419:Nerve Tissue Proteins / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000209:etiology; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology*; D058112:Septins; D051843:Synucleins; D014162:Transfection; D051844:alpha-Synuclein
D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C118958:SNCAIP protein, human; C497605:Snca protein, mouse; C498464:Sncaip protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C492027:SEPTIN4 protein, human; C115474:Sept4 protein, mouse; D058112:Septins