title: Familial amyotrophic lateral sclerosis-linked mutant SOD1 aberrantly interacts with tubulin.
abstract: Mutations in the Cu,Zn-superoxide dismutase (SOD1) gene cause 20-25% of familial amyotrophic lateral sclerosis (ALS). Mutant SOD1 causes motor neuron degeneration through toxic gain-of-function(s). However, the direct molecular targets of mutant SOD1, underlying its toxicity, are not fully understood. In this study, we found that alpha/beta-tubulin is one of the major mutant SOD1-interacting proteins, but that wild-type SOD1 does not interact with it. The interaction between tubulin and mutant SOD1 was detected in the spinal cords of mutant G93A SOD1 transgenic mice before the onset of symptoms. Tubulin interacted with amino acid residues 1-23 and 116-153 of SOD1. Overexpression of mutant SOD1 resulted in the accumulation of tubulin in detergent-insoluble fractions. In a cell-free system, mutant SOD1 modulated tubulin polymerization, while wild-type SOD1 did not. Since tightly regulated microtubule dynamics is essential for neurons to remain viable, alpha/beta-tubulin could be an important direct target of mutant SOD1.
authors: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan. kabuta@ncnp.go.jp
authors: Tomohiro
authors: T
authors: Kabuta
authors: Aiko
authors: A
authors: Kinugawa
authors: Yukihiro
authors: Y
authors: Tsuchiya
authors: Chihana
authors: C
authors: Kabuta
authors: Rieko
authors: R
authors: Setsuie
authors: Minako
authors: M
authors: Tateno
authors: Toshiyuki
authors: T
authors: Araki
authors: Keiji
authors: K
authors: Wada
mesh_terms: D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism*
chemical_list: D014404:Tubulin; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase