Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein.
Alpha-synuclein is a major constituent of pathological intracellular inclusion bodies, a common feature of several neurodegenerative diseases. Two missense mutations in the alpha-synuclein gene have been identified in confirmed autosomal-dominant familial Parkinson's disease, which segregate with the illness. However, the physiological function of alpha-synuclein remains unknown. After biochemical investigations we have revealed tubulin to be an alpha-synuclein associated/binding protein. Here, we show that alpha-synuclein induces polymerization of purified tubulin into microtubules. Mutant forms of alpha-synuclein lose this potential. The binding site of alpha-synuclein to tubulin is identified, and co-localization of alpha-synuclein with microtubules is shown in cultured cells. To our knowledge, this is the first demonstration of microtubule-polymerizing activity of alpha-synuclein. Now we can see a striking resemblance between alpha-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 alpha-synuclein may provide a new dimension in researches into the mechanisms of alpha-synuclein-associated neurodegenerative diseases.
Alim
Muhammad Abdul
MA
Department of Neural Plasticity, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, 156-8585, Japan.
Ma
Qiu-Lan
QL
Takeda
Kazuya
K
Aizawa
Takako
T
Matsubara
Mamoru
M
Nakamura
Minako
M
Asada
Akiko
A
Saito
Taro
T
Kaji
Hiroyuki
H
Yoshii
Mitsunobu
M
Hisanaga
Shinichi
S
Uéda
Kenji
K
D000429:Alcohol Oxidoreductases; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019556:COS Cells / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D042541:Intracellular Space / Q000378:metabolism / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020125:Mutation, Missense / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D013552:Swine; D051843:Synucleins; D014162:Transfection / Q000379:methods; D051844:alpha-Synuclein; D016875:tau Proteins / Q000378:metabolism
D017931:DNA Primers; D004268:DNA-Binding Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D051843:Synucleins; D051844:alpha-Synuclein; D016875:tau Proteins; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein