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

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $568,064

## Abstract

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.

## Key facts

- **NIH application ID:** 10890169
- **Project number:** 5R01NS133688-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Bobby Thomas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $568,064
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890169

## Citation

> US National Institutes of Health, RePORTER application 10890169, Molecular Mechanisms of Oxidation Resistance 1 in Parkinson's disease and Lewy Body Dementia (5R01NS133688-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10890169. Licensed CC0.

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