Neurobiology of Disease Mimicking Phosphorylation at Serine 87 Inhibits the Aggregation of Human -Synuclein and Protects against Its Toxicity in a Rat Model of Parkinson’s Disease

Several lines of evidence suggest that phosphorylation of -synuclein ( -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 -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 -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 -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 -syn aggregates, dystrophic fibers, and motor impairment. Together, our data demonstrate, for the first time, that mimicking phosphorylation at S87 inhibits -syn aggregation and protects against -syn-induced toxicity in vivo, suggesting that phosphorylation at this residue would play an important role in controlling -syn neuropathology. In addition, our results provide strong evidence for a direct correlation between -syn-induced neurotoxicity, fiber pathology, and motor impairment and the extent of -syn aggregation in vivo, suggesting that lowering -syn levels and/or blocking its aggregation are viable therapeutic strategies for the treatment of Parkinson’s disease and related synucleinopathies.