Α-synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism. (July 2021)

• Record Type: Journal Article
• Authors: Ghosh, Soumitra; Won, Seok Joon; Wang, Jiejie; Fong, Rebecca; Butler, Nicholas J.M.; Moss, Arianna; Wong, Candance; Pan, June; Sanchez, Jennifer; Huynh, Annie; Wu, Long; Manfredsson, Fredric P.; Swanson, Raymond A.
• Is Part Of: Progress in neurobiology. Volume 202(2021)
• Publication Date: 2021-07
• Subjects: c-Abl cellular homolog of the v-Abl oncogene of the Abelson murine leukemia virus -- EAAT3 excitatory amino acid transporter 3 -- HNE hydroxynonenal -- MAP microtubule-associated protein -- NAC N-acetyl cysteine -- PD Parkinson's disease -- PFF pre-formed α-synuclein fibrils -- PVDF polyvinylidene fluoride -- rAAV recombinant adeno-associated virus -- SDS sodium dodecyl sulfate -- TH tyrosine hydroxylase; Excitatory amino acid transporter 3 -- Parkinson's disease -- Gene-Environment interaction -- Glutathione -- SLC1A1; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2021.102070
• Languages: English
• ISSNs: 0301-0082

Abstract

Graphical abstract: Highlights: α-synuclein aggregates induce redox stress and glutathione depletion. Redox stress in turn drives activation of the protein kinase, c-Abl. c-Abl activation further promotes α-synuclein aggregation and neuronal loss N-acetyl cysteine supports neuronal glutathione synthesis. N-acetyl cysteine suppresses c-Abl activation, α-synuclein aggregation, and neuronal loss. 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.