Molecular Mechanisms of Oxidation Resistance 1 in Parkinson's disease and Lewy Body Dementia

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PROJECT SUMMARY Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the loss of nigral dopaminergic neurons and the presence of fibrillar cytoplasmic inclusions composed of alpha-synuclein (αS) known as Lewy bodies. Neurodegeneration in PD is not limited to only the nigral dopaminergic neurons but also involves cells located in other regions of the neural network. Besides motor symptoms, cognitive impairments are one of the essential non-motor manifestations of PD that severely affects the quality of life and has substantial economic consequences. The emerging view suggests that the abnormalities in αS are a strong pathological correlate for motor and neurocognitive dysfunction in PD and Dementia with Lewy Bodies (DLB), a disease clinically and pathologically related to PD. While the mechanism by which αS pathology leads to neuronal dysfunction is unknown, existing evidence suggests that compromised redox homeostasis, defects in protein quality control, mitochondrial dysfunction, and neuroinflammation cause αS aggregation and neurodegeneration in PD and DLB. Oxidation resistance 1 (Oxr1) has emerged as a vital protein that orchestrates a multifaceted response to modulate many of the etiological pathways involved in PD and α-synucleinopathies. The mechanism underlying this process, however, remains poorly understood. Our studies show that Oxr1 overexpression is neuroprotective in preclinical PD models due to its regulation of the lysosomal proton pump vacuolar-ATPase (V-ATPase) which is critical for lysosomal function. We show that Oxr1 interacts with V-ATPase and that neurons lacking Oxr1 exhibit an increase in lysosomal pH, reduce lysosomal proteolytic activity, and exacerbate neurodegeneration in PD preclinical models. We employed innovative systems biology approaches to compare similarities in affected pathways between single-nuclei transcriptomic data from human DLB patients and proteomic data from preclinical models of α-synucleinopathy overexpressing Oxr1. Our analysis revealed that besides lysosomal pathways, Oxr1 overexpression modulated novel non-canonical pathways involved in neuronal survival due to the overabundance of pathway drivers in preclinical PD and human DLB. We hypothesize that Oxr1 is a key mediator of intrinsic protective pathways in PD and DLB. Using rodent models of α-synucleinopathy, we propose to test the hypothesis that Oxr1 overexpression ameliorates αS-induced PD and DLB by modulating both lysosomal and non-canonical neuroprotective pathways. The proposed studies will provide novel insights into molecular mechanisms underlying Oxr1-mediated neuroprotection and identify new targets for therapeutic interventions in PD and DLB.