Disrupting pathogenic interactions between α-synuclein, c-Abl, and redox stress

Abstract

Objective: Redox stress, c-Abl activation, and α -synuclein aggregates each independently contribute to neurodegeneration in Parkinson's disease. Interactions between these factors may underlie convergent and feed-forward mechanisms of disease progression. Methods:α -synuclein aggregate formation was induced in neuronal cultures and mouse substantia nigra by exposure to pre-formed human α -synuclein fibrils or by AAV-mediated over-expression of α -synuclein. Aggregate formation, c-Abl activation, redox stress, and neurodegeneration were evaluated by immunohistochemistry and Western blots, and mouse motor function was evaluated using the rota-rod and pole tests. To suppress redox stress, cultures and mice were treated with N-acetyl cysteine, a thiol repletion agent that supports neuronal glutathione metabolism. Results: In primary neuron cultures, the formation of α -synuclein aggregates led to redox stress and c-Abl activation. Redox stress alone, in the absence of α -synuclein aggregates, was also sufficient to induced c-Abl activation. N-acetyl cysteine suppressed redox stress, and likewise suppressed both c-Abl activation and α -synuclein aggregation. A similar pattern was observed in the two mouse models of Parkinson's disease. In both models, α synuclein aggregates in the substantia nigra were accompanied by redox stress, c-Abl activation, dopaminergic neurodegeneration and motor impairment, all of which were attenuated in mice treated with oral N-acetyl cysteine.Interpretation: These results indicate that α -synuclein aggregates induce c-Abl activation by a redox stress mechanism. c-Abl in turn promotes α -synuclein aggregation, and this potentially feed-forward process can be blocked by N-acetyl cysteine. The findings thus add mechanistic support for N-acetyl cysteine as a therapeutic for Parkinson's disease.