1. α-synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism
- Author
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Ghosh, Soumitra, Won, Seok Joon, Wang, Jiejie, Fong, Rebecca, Butler, Nicholas JM, Moss, Arianna, Wong, Candance, Pan, June, Sanchez, Jennifer, Huynh, Annie, Wu, Long, Manfredsson, Fredric P, and Swanson, Raymond A
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Neurodegenerative ,Brain Disorders ,Parkinson's Disease ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Animals ,Cysteine ,Dopamine ,Dopaminergic Neurons ,Mice ,Oxidation-Reduction ,Parkinson Disease ,Substantia Nigra ,alpha-Synuclein ,Excitatory amino acid transporter 3 ,Parkinson's disease ,Gene-Environment interaction ,Glutathione ,Parkinson’s disease ,SLC1A1 ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Oxidative stress and α-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 α-synuclein fibrils (PFFs) were used to induce α-synuclein aggregation in neuronal cultures. Exposure to PFFs induced oxidative stress and c-Abl activation in wild-type neurons. By contrast, α-synuclein - deficient neurons, which cannot form α-synuclein aggregates, failed to exhibit either oxidative stress or c-Abl 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 α-synuclein aggregation. Parallel findings were observed in mouse brain: PFF-induced α-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 α-synuclein overexpression as an alternative means of driving α-synuclein aggregation in vivo. These findings show that α-synuclein aggregates induce c-Abl activation by a redox stress mechanism. c-Abl activation in turn promotes α-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.
- Published
- 2021