Changes in α-Synuclein Posttranslational Modifications in an AAV-Based Mouse Model of Parkinson’s Disease

Abstract

Parkinson’s disease (PD) pathology is characterized by the loss of dopaminergic neurons of the nigrostriatal system and accumulation of Lewy bodies (LB) and Lewy neurites (LN), inclusions mainly composed of alpha-synuclein (α-Syn) fibrils. Studies linking the occurrence of mutations and multiplications of the α-Syn gene (SNCA) to the onset of PD support that α-Syn deposition may play a causal role in the disease, in line with the hypothesis that disease progression may correlate with the spreading of LB pathology in the brain. Interestingly, LB accumulate posttranslationally modified forms of α-Syn, suggesting that α-Syn posttranslational modifications impinge on α-Syn aggregation and/or toxicity. Here, we aimed at investigating changes in α-Syn phosphorylation, nitration and acetylation in mice subjected to nigral stereotaxic injections of adeno-associated viral vectors inducing overexpression of human α-Syn (AAV-hα-Syn), that model genetic PD with SNCA multiplications. We detected a mild increase of serine (Ser) 129 phosphorylated α-Syn in the substantia nigra (SN) of AAV-hα-Syn-injected mice in spite of the previously described marked accumulation of this PTM in the striatum. Following AAV-hα-Syn injection, tyrosine (Tyr) 125/136 nitrated α-Syn accumulation in the absence of general 3-nitrotirosine (3NT) or nitrated-Tyr39 α-Syn changes and augmented protein acetylation abundantly overlapping with α-Syn immunopositivity were also detected.

Keywords

• Parkinson’s disease
• alpha-synuclein
• posttranslational modifications
• phosphorylation
• nitration
• acetylation