Association of the Cytoskeletal GTP-binding Protein Sept4/H5 with Cytoplasmic Inclusions Found in Parkinson's Disease and Other Synucleinopathies

• Published in: The Journal of biological chemistry 2003-06, Vol.278 (26), p.24095-24102
• Main Authors: Ihara, Masafumi, Tomimoto, Hidekazu, Kitayama, Hitoshi, Morioka, Yoko, Akiguchi, Ichiro, Shibasaki, Hiroshi, Noda, Makoto, Kinoshita, Makoto
• Format: Article
• Language: English
• Subjects: Aged; alpha-Synuclein; Animals; Biomarkers, Tumor - metabolism; Biomarkers, Tumor - physiology; Brain - pathology; Carrier Proteins - physiology; Cell Death; Cell Line; Cytoskeletal Proteins; Cytoskeleton - chemistry; GTP Phosphohydrolases - metabolism; GTP Phosphohydrolases - physiology; GTP-Binding Proteins - metabolism; Humans; Inclusion Bodies - chemistry; Intracellular Signaling Peptides and Proteins; Lewy Bodies - chemistry; Mice; Nerve Tissue Proteins - physiology; Neurodegenerative Diseases - etiology; Parkinson Disease - etiology; Parkinson Disease - pathology; septin 4; Septins; synuclein; Synucleins; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M301352200

α-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 α-synuclein can also be co-immunoprecipitated from normal human brain lysates. When co-expressed in cultured cells, FLAG-tagged Sept4 and Myc-tagged α-synuclein formed detergent-insoluble complex, and upon treatment with a proteasome inhibitor, they formed Lewy body-like cytoplasmic inclusions. The tagged Sept4 and α-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, α-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 α-synuclein-associated neurodegenerative disorders.