Microtubule depolymerization suppresses alpha-synuclein accumulation in a mouse model of multiple system atrophy.
Multiple system atrophy (MSA) is a neurodegenerative disease caused by an accumulation of alpha-synuclein (alpha-syn) in oligodendrocytes. Little is known about the cellular mechanisms by which alpha-syn accumulation causes neuronal degeneration in MSA. Our previous research, however, revealed that in a mouse model of MSA, oligodendrocytic inclusions of alpha-syn induced neuronal accumulation of alpha-syn, as well as progressive neuronal degeneration. Here we identify the mechanisms that underlie neuronal accumulation of alpha-syn in a mouse MSA model. We found that the alpha-syn protein binds to beta-III tubulin in microtubules to form an insoluble complex. The insoluble alpha-syn complex progressively accumulates in neurons and leads to neuronal dysfunction. Furthermore, we demonstrated that the neuronal accumulation of insoluble alpha-syn is suppressed by treatment with a microtubule depolymerizing agent. The underlying pathological process appeared to also be inhibited by this treatment, providing promise for future therapeutic approaches.
Nakayama
Kimiko
K
Laboratory of Research Resources, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3 Gengo, Morioka-cho, Obu-shi, Aichi 474-7522, Japan.
Suzuki
Yasuyo
Y
Yazawa
Ikuru
I
D000818:Animals; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism* / Q000473:pathology; D019578:Multiple System Atrophy / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism*
D051844:alpha-Synuclein