-synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism

Oxidative stress and alpha-synuclein aggregation both drive neurodegeneration in Parkinson's disease, and the protein kinase c-Abl provides a potential amplifying link between these pathogenic factors. Suppressing interactions between these factors may thus be a viable therapeutic approach for this disorder. To evaluate this possibility, pre-formed alpha-synuclein fibrils (PFFs) were used to induce alpha-synuclein aggregation in neuronal cultures. Exposure to PFFs induced oxidative stress and c-Abl activation in wild-type neurons. By contrast, alpha-synuclein - deficient neurons, which cannot form alpha-synuclein aggregates, failed to exhibit either oxidative stress or cAbl activation. N-acetyl cysteine, a thiol repletion agent that supports neuronal glutathione metabolism, suppressed the PFF - induced redox stress and c-Abl activation in the wild-type neurons, and likewise suppressed alpha-synuclein aggregation. Parallel findings were observed in mouse brain: PFF-induced alpha-synuclein aggregation in the substantia nigra was associated with redox stress, c-Abl activation, and dopaminergic neuronal loss, along with microglial activation and motor impairment, all of which were attenuated with oral N-acetyl cysteine. Similar results were obtained using AAV-mediated alpha-synuclein overexpression as an alternative means of driving alpha-synuclein aggregation in vivo. These findings show that alpha-synuclein aggregates induce c-Abl activation by a redox stress mechanism. c-Abl activation in turn promotes alpha-synuclein aggregation, in a feed-forward interaction. The capacity of N-acetyl cysteine to interrupt this interaction adds mechanistic support its consideration as a therapeutic in Parkinson's disease.