Mimicking phosphorylation at serine 87 inhibits the aggregation of human α-synuclein and protects against its toxicity in a rat model of parkinson's disease

Abid Oueslati, Katerina E. Paleologou, Bernard L. Schneider, Patrick Aebischer, Hilal A. Lashuel

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Abstract

Several lines of evidence suggest that phosphorylation of α -synuclein (α -syn) at S87 or S129 may play an important role in regulating its aggregation, fibrillogenesis, Lewy body formation, and neurotoxicity in vivo. However, whether phosphorylation at these residues enhances or protects against α -syn toxicity in vivo remains unknown. In this study, we investigated the cellular and behavioral effect of overexpression of wild-type (WT), S87A, and S87E α -syn to block or to mimic S87 phosphorylation, respectively, in the substantia nigra of Wistar rats using recombinant adeno-associated vectors. Our results revealed that WT and S87A overexpression induced α -syn aggregation, loss of dopaminergic neurons, and fiber pathology. These neuropathological effects correlated well with the induction of hemi-parkinsonian motor symptoms. Strikingly, overexpression of the phosphomimic mutant S87E did not show any toxic effect on dopaminergic neurons and resulted in significantly less α -syn aggregates, dystrophic fibers, and motor impairment. Together, our data demonstrate, for the first time, that mimicking phosphorylation at S87 inhibits α -syn aggregation and protects against α -syn-induced toxicity in vivo, suggesting that phosphorylation at this residue would play an important role in controlling α -syn neuropathology. In addition, our results provide strong evidence for a direct correlation between α -syn-induced neurotoxicity, fiber pathology, and motor impairment and the extent of α -syn aggregation in vivo, suggesting that lowering α -syn levels and/or blocking its aggregation are viable therapeutic strategies for the treatment of Parkinson's disease and related synucleinopathies.

Original languageEnglish
Pages (from-to)1536-1544
Number of pages9
JournalJournal of Neuroscience
Volume32
Issue number5
DOIs
Publication statusPublished - 1 Feb 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Neuroscience(all)

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