Accumulation of α-synuclein triggered by presynaptic dysfunction

Abstract

Pathological examination of dementia with Lewy bodies patients identified the presence of abnormal α-Synuclein (aSyn) aggregates in the presynaptic terminals. aSyn is involved in the regulation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. Importantly, aSyn-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 aSyn using Snap25S187A/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 aSyn 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 aSyn 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 aSyn, and probably is an important pathomechanism of α-Synucleinopathies. © 2012 the authors.