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Originally published In Press as doi:10.1074/jbc.M301352200 on April 14, 2003

J. Biol. Chem., Vol. 278, Issue 26, 24095-24102, June 27, 2003
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Association of the Cytoskeletal GTP-binding Protein Sept4/H5 with Cytoplasmic Inclusions Found in Parkinson's Disease and Other Synucleinopathies*

Masafumi Ihara {ddagger} § ¶, Hidekazu Tomimoto {ddagger}, Hitoshi Kitayama §, Yoko Morioka §, Ichiro Akiguchi {ddagger}, Hiroshi Shibasaki {ddagger}, Makoto Noda § and Makoto Kinoshita §

From the {ddagger}Department of Neurology, Kyoto University Graduate School of Medicine, Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 and the §Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan

{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.

Received for publication, February 6, 2003 , and in revised form, April 11, 2003.

* This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to H. T. and M. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 81-75-7513766; Fax: 81-75-7513265; E-mail: ihara{at}kuhp.kyoto-u.ac.jp.


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