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Parkin interacting substrate phosphorylation by c-Abl drives dopaminergic neurodegeneration
Brain  (IF13.501),  Pub Date : 2021-09-28, DOI: 10.1093/brain/awab356
Hyojung Kim, Jeong-Yong Shin, Areum Jo, Ji Hun Kim, Sangwook Park, Jeong-Yun Choi, Ho Chul Kang, Valina L Dawson, Ted M Dawson, Joo-Ho Shin, Yunjong Lee

Aberrant activation of the non-receptor kinase c-Abl is implicated in the development of pathogenic hallmarks of Parkinson’s disease, such as α-synuclein aggregation and progressive neuronal loss. c-Abl-mediated phosphorylation and inhibition of parkin ligase function lead to accumulation of parkin-interacting substrate that mediates α-synuclein pathology-initiated dopaminergic neurodegeneration. Here we show that, in addition to parkin interacting substrate accumulation, c-Abl phosphorylation of parkin interacting substrate is required for parkin interacting substrate-induced cytotoxicity. c-Abl-mediated phosphorylation of parkin interacting substrate at Y137 (within the Krüeppel-associated box domain) drives its association with KAP1 and the repression of genes with diverse functions in pathways such as chromatin remodeling and p53-dependent cell death. One phosphorylation-dependent parkin interacting substrate target, MDM4 (a p53 inhibitor that associates with MDM2; also known as MDMX), is transcriptionally repressed in an histone deacetylase-dependent manner via parkin interacting substrate binding to insulin response sequence motifs within the MDM4 promoter. Virally-induced parkin interacting substrate transgenic mice develop c-Abl activity-dependent Parkinson’s disease features such as motor deficits, dopaminergic neuron loss, and neuroinflammation. Parkin interacting substrate expression in the midbrain resulted in c-Abl activation, parkin interacting substrate phosphorylation, MDM4 repression, and p53 activation, all of which are blocked by the c-Abl inhibitor nilotinib. Importantly, we also observed aberrant c-Abl activation and parkin interacting substrate phosphorylation along with parkin interacting substrate accumulation in the midbrain of adult parkin knockout mice, implicating c-Abl in recessive Parkinson’s disease. Inhibition of c-Abl or parkin interacting substrate phosphorylation by nilotinib or Y137F-parkin interacting substrate expression in adult parkin knockout mice blocked MDM4 repression and p53 activation, preventing motor deficits, and dopaminergic neurodegeneration. Finally, we found correlative increases in parkin interacting substrate phosphorylation, MDM4 repression, and p53 activation in postmortem Parkinson’s disease brains, pointing to clinical relevance of the c-Abl-parkin interacting substrate-MDM4-p53 pathway. Taken together, our results describe a novel mechanism of epigenetic regulation of dopaminergic degeneration downstream of pathologic c-Abl activation in Parkinson’s disease. Since c-Abl activation has been shown in sporadic Parkinson’s disease, parkin interacting substrate phosphorylation might serve as both a useful biomarker and a potential therapeutic target to regulate neuronal loss in Parkinson’s disease.