Demonstration of a role for α-synuclein as a functional microtubule-associated protein

Article type: Research Article

Authors: Alim, Muhammad Abdul^{a; **} | Ma, Qiu-Lan^{a; b; ***} | Takeda, Kazuya^{c; ****} | Aizawa, Takako^a | Matsubara, Mamoru^d | Nakamura, Minako^e | Asada, Akiko^f | Saito, Taro^f | xKaji, Mitsunobu^c | Yoshii, Mitsunobu^a | Hisanaga, Shinichi^f | Uéda, Kenji^{a; *}

Affiliations: [a] Department of Neural Plasticity, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan | [b] Department of Neurobiology and Neurology, Xuanwu Hospital, Capital University of Medical Sciences, Beijing 100053, China | [c] Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan | [d] RIKEN Harima Institute, 1-1-1 Kouto, Mikazuki-cho, Sayo-gun 679-5148, Japan | [e] Electron Microscopy Center, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan | [f] Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan

Correspondence: [*] Corresponding author: Kenji Uéda, Ph.D., Department of Neural Plasticity, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan. Tel.: +81 3 3304 5701 (Ext. 511); Fax: +81 3 3329 8035; E-mail: [email protected].

Note: [**] Department of Psychiatry and Pathology, NYU School of Medicine, New York, NY 10016, USA

Note: [***] Departments of Medicine and Neurology, UCLA School of Medicine, 16111 Plummer St., North Hills, CA 91343, USA

Note: [****] National Institute for Longevity Sciences, Morioka, Obu 474-8522, Japan

Abstract: α-Synuclein is a major constituent of pathological intracellular inclusion bodies, a common feature of several neurodegenerative diseases. Two missense mutations in the α-synuclein gene have been identified in confirmed autosomal-dominant familial Parkinson's disease, which segregate with the illness. However, the physiological function of α-synuclein remains unknown. After biochemical investigations we have revealed tubulin to be an α-synuclein associated/binding protein. Here, we show that α-synuclein induces polymerization of purified tubulin into microtubules. Mutant forms of α-synuclein lose this potential. The binding site of α-synuclein to tubulin is identified, and co-localization of α-synuclein with microtubules is shown in cultured cells. To our knowledge, this is the first demonstration of microtubule-polymerizing activity of α-synuclein. Now we can see a striking resemblance between α-synuclein and tau: both have the same physiological function and pathological features, making abnormal structures in diseased brains known as synucleinopathies and tauopathies. The discovery of a physiological role for α-synuclein may provide a new dimension in researches into the mechanisms of α-synuclein-associated neurodegenerative diseases.

Keywords: lewy body, MAP, neurodegeneration, Parkinson, synuclein, tubulin

DOI: 10.3233/JAD-2004-6412

Journal: Journal of Alzheimer's Disease, vol. 6, no. 4, pp. 435-442, 2004