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- Title
Accumulation of ɑ-Synuclein Triggered by Presynaptic Dysfunction.
- Authors
Nakata, Yasuto; Yasuda, Toru; Fukaya, Masahiro; Yamamori, Saori; Itakura, Makoto; Nihira, Tomoko; Hayakawa, Hideki; Kawanami, Aya; Kataoka, Masakazu; Nagai, Makiko; Sakagami, Hiroyuki; Takahashi, Masami; Mizuno, Yoshikuni; Mochizuki, Hideki
- Abstract
Pathological examination of dementia with Lewy bodies patients identified the presence of abnormal ɑ-synuclein (uSyn) aggregates in the presynaptic terminals. aSyn is involved in the regulation of soluble AT-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. Importantly, aSyn-transgenic mouse and postmortem examination of patients with Parkinson's disease have dem-onstrated the abnormal distribution of SNARE protein in presynaptic terminals. In this study, we investigated the effects of SNARE dysfunction on endogenous aSyn using Snap25s187A/s187A mutant mice. These mice have homozygous knock-in gene encoding unphos-phorylatable S187ɑ-substituted synaptosomal-associated protein of 25 kDa (SNAP-25). The mice displayed a significant age-dependent change in the distribution of aSyn and its Ser129-phosphorylated form in abnormally hypertrophied glutamatergic nerve terminals in the striatum. Electron-microscopic analysis revealed the abnormally condensed synaptic vesicles with concomitant mislocalization of aSyn protein to the periactive zone in the glutamatergic nerve terminals. However, the Snap25s187A/s187A mutant mouse harbored no abnor-malities in the nigrostriatal dopaminergic neurons. Our present results suggest that SNARE dysfunction is the initial trigger of mislocal-ization and accumulation of aSyn, and probably is an important pathomechanism of ɑ-synucleinopathies.
- Subjects
SYNUCLEINS; PRESYNAPTIC receptors; PATHOLOGICAL anatomy; DEMENTIA patients; LEWY body dementia; PARKINSON'S disease; PROTEIN receptors; LABORATORY mice; PATIENTS
- Publication
Journal of Neuroscience, 2012, Vol 32, Issue 48, p17186
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.2220-12.2012