title: Accumulation of α-synuclein triggered by presynaptic dysfunction.
abstract: Pathological examination of dementia with Lewy bodies patients identified the presence of abnormal α-synuclein (αSyn) aggregates in the presynaptic terminals. αSyn is involved in the regulation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. Importantly, αSyn-transgenic mouse and postmortem examination of patients with Parkinson'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 αSyn using Snap25(S187A/S187A) mutant mice. These mice have homozygous knock-in gene encoding unphosphorylatable S187A-substituted synaptosomal-associated protein of 25 kDa (SNAP-25). The mice displayed a significant age-dependent change in the distribution of αSyn 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 αSyn protein to the periactive zone in the glutamatergic nerve terminals. However, the Snap25(S187A/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 αSyn, and probably is an important pathomechanism of α-synucleinopathies.
authors.affiliation: Department of Neurology, Division of Neuroregenerative Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Nakata
authors.forename: Toru
authors.initials: T
authors.lastname: Yasuda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukaya
authors.forename: Saori
authors.initials: S
authors.lastname: Yamamori
authors.forename: Makoto
authors.initials: M
authors.lastname: Itakura
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nihira
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayakawa
authors.forename: Aya
authors.initials: A
authors.lastname: Kawanami
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kataoka
authors.forename: Makiko
authors.initials: M
authors.lastname: Nagai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakagami
authors.forename: Masami
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000473:pathology; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D050825:Synaptosomal-Associated Protein 25; D051844:alpha-Synuclein