Selective loss of nigral dopamine neurons induced by overexpression of truncated human alpha-synuclein in mice.
Parkinson's disease is characterized by loss of nigral dopaminergic neurons and presence of Lewy bodies, whose major component is alpha-synuclein. In the present study, we generated transgenic mice termed Syn130m that express truncated human alpha-synuclein (amino acid residue number: 1-130) in dopaminergic neurons. Notably, dopaminergic neurons were selectively diminished in the substantia nigra pars compacta of Syn130m, while transgenic mice that expressed comparable amount of full-length human alpha-synuclein did not develop such pathology. Therefore, the truncation of human alpha-synuclein seems to be primarily responsible for the loss of nigral dopaminergic neurons. The nigral pathology resulted in impairment of axon terminals in the striatum and concomitant decrease in striatal dopamine content. Behaviorally, spontaneous locomotor activities of Syn130m were reduced, but the abnormality was ameliorated by treatment with L-DOPA. The loss of nigral dopaminergic neurons was not progressive and seemed to occur during embryogenesis along with the onset of expression of the transgene. Our results indicate that truncated human alpha-synuclein is deleterious to the development and/or survival of nigral dopaminergic neurons.
Wakamatsu
Masaki
M
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Yoshino-cho 1-403, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
Ishii
Aiko
A
Iwata
Shingo
S
Sakagami
Junko
J
Ukai
Yuriko
Y
Ono
Mieko
M
Kanbe
Daiji
D
Muramatsu
Shin-ichi
S
Kobayashi
Kazuto
K
Iwatsubo
Takeshi
T
Yoshimoto
Makoto
M
D000818:Animals; D002452:Cell Count / Q000379:methods; D004298:Dopamine / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D051381:Rats; D017384:Sequence Deletion; D013378:Substantia Nigra / Q000166:cytology / Q000502:physiology*; D051844:alpha-Synuclein / Q000235:genetics*
D051844:alpha-Synuclein; D004298:Dopamine