Motor impairment and aberrant production of neurochemicals in human alpha-synuclein A30P+A53T transgenic mice with alpha-synuclein pathology.
Missense point mutations, duplication and triplication in the alpha-synuclein (alphaSYN) gene have been identified in familial Parkinson's disease (PD). Familial and sporadic PD show common pathological features of alphaSYN pathologies, e.g., Lewy bodies (LBs) and Lewy neurites (LNs), and a loss of dopaminergic neurons in the substantia nigra that leads to motor disturbances. To elucidate the mechanism of alphaSYN pathologies, we generated TgalphaSYN transgenic mice overexpressing human alphaSYN with double mutations in A30P and A53T. Human alphaSYN accumulated widely in neurons, processes and aberrant neuronal inclusion bodies. Sarcosyl-insoluble alphaSYN, as well as phosphorylated, ubiquitinated and nitrated alphaSYN, was accumulated in the brains. Significantly decreased levels of dopamine (DA) were recognized in the striatum. Motor impairment was revealed in a rotarod test. Thus, TgalphaSYN is a useful model for analyzing the pathological cascade from aggregated alphaSYN to motor disturbance, and may be useful for drug trials.
Ikeda
Masaki
M
Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Kawarabayashi
Takeshi
T
Harigaya
Yasuo
Y
Sasaki
Atsushi
A
Yamada
Shuichi
S
Matsubara
Etsuro
E
Murakami
Tetsuro
T
Tanaka
Yuya
Y
Kurata
Tomoko
T
Wuhua
Xu
X
Ueda
Kenji
K
Kuribara
Hisashi
H
Ikarashi
Yasushi
Y
Nakazato
Yoichi
Y
Okamoto
Koichi
K
Abe
Koji
K
Shoji
Mikio
M
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology*; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045442:Rotarod Performance Test; D012701:Serotonin / Q000378:metabolism; D054875:Ubiquitination; D051844:alpha-Synuclein / Q000235:genetics*
D012333:RNA, Messenger; D051844:alpha-Synuclein; D012701:Serotonin; D000109:Acetylcholine; D004298:Dopamine