Abstract |
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.
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Authors | Masaki Ikeda, Takeshi Kawarabayashi, Yasuo Harigaya, Atsushi Sasaki, Shuichi Yamada, Etsuro Matsubara, Tetsuro Murakami, Yuya Tanaka, Tomoko Kurata, Xu Wuhua, Kenji Ueda, Hisashi Kuribara, Yasushi Ikarashi, Yoichi Nakazato, Koichi Okamoto, Koji Abe, Mikio Shoji |
Journal | Brain research
(Brain Res)
Vol. 1250
Pg. 232-41
(Jan 23 2009)
ISSN: 1872-6240 [Electronic] Netherlands |
PMID | 18992718
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- RNA, Messenger
- alpha-Synuclein
- Serotonin
- Acetylcholine
- Dopamine
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Topics |
- Acetylcholine
(metabolism)
- Animals
- Blotting, Western
- Brain
(metabolism, pathology)
- Corpus Striatum
(metabolism)
- Dopamine
(metabolism)
- Humans
- Immunohistochemistry
- Inclusion Bodies
(metabolism)
- Mice
- Mice, Transgenic
- Motor Activity
(physiology)
- Mutation
- Neurons
(cytology, metabolism)
- Phosphorylation
- RNA, Messenger
(metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Rotarod Performance Test
- Serotonin
(metabolism)
- Ubiquitination
- alpha-Synuclein
(genetics)
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