Accumulation of alpha-Synuclein Triggered by Presynaptic Dysfunction

作者：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^*

来源：Journal of Neuroscience, 2012, 32(48): 17186-17196.

DOI：10.1523/JNEUROSCI.2220-12.2012

Pathological examination of dementia with Lewy bodies patients identified the presence of abnormal alpha-synuclein (alpha Syn) aggregates in the presynaptic terminals. alpha Syn is involved in the regulation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. Importantly, alpha Syn-transgenic mouse and postmortem examination of patients with Parkinson%26apos;s disease have demonstrated the abnormal distribution of SNARE protein in presynaptic terminals. In this study, we investigated the effects of SNARE dysfunction on endogenous alpha Syn using Snap25(S187A/S187A) mutant mice. These mice have homozygous knock-in gene encoding unphos-phorylatable S187A-substituted synaptosomal-associated protein of 25 kDa (SNAP-25). The mice displayed a significant age-dependent change in the distribution of alpha Syn and its Ser(129)-phosphorylated form in abnormally hypertrophied glutamatergic nerve terminals in the striatum. Electron-microscopic analysis revealed the abnormally condensed synaptic vesicles with concomitant mislocalization of alpha Syn protein to the periactive zone in the glutamatergic nerve terminals. However, the Snap25S187A/S187A mutant mouse harbored no abnormalities in the nigrostriatal dopaminergic neurons. Our present results suggest that SNARE dysfunction is the initial trigger of mislocalization and accumulation of alpha Syn, and probably is an important pathomechanism of alpha-synucleinopathies.

• 出版日期2012-11-28