USP13-Mediated Dopaminergic Neurodegeneration
Abstract
Mutations and inactivation of parkin, a ubiquitin E3 ligase, induce Parkinson s disease (PD). Post-translational modifications affect parkin activity and stability, which are important for mitochondrial quality control and cellular defense. The deubiquitination pathway can regulate mitochondrial quality control via regulation of parkin stability and activity. However, ubiquitin-specific protease 13 (USP13)-mediated deubiquitination of parkin remains unclear. In a preliminary study, we identified USP13 as the deubiquitinase that regulates parkin stability via deubiquitination of parkin. In addition, preliminary studies indicate that overexpression of USP13 protects against, and knockdown of USP13 exacerbates, cell toxicity induced by oxidative stress by 6-OHDA in a cell culture system. As such, further characterization of USP13 as a key modulator involved in regulating parkin stability allows us to understand why decreased parkin protein levels and enzyme activity exist in neurodegeneration of PD and provides a new molecular target for the development of PD therapeutics. To address this, we propose to determine the effects of USP13 manipulation (overexpression or depletion) in dopaminergic neurodegeneration, LBs pathology, and mitochondrial dysfunction induced by 6-OHDA or alpha-synuclein PFF in vivo and in human dopaminergic neurons. This work will broaden our understanding of the previously overlooked but significant pathogenic mechanism of PD caused by neurotoxin exposure, using rodent and human model systems. This research will identify the mechanisms by which USP13 overexpression protects dopaminergic neurons or USP13 depletion contributes to neurodegeneration in multiple toxin models of PD and human dopaminergic neurons. The results will provide a new insight into the role of USP13 in PD pathogenesis caused by neurotoxin exposure. This research leads to the discovery of a therapeutic intervention for PD. USP13 can be developed as a disease-modifying agent for PD due to its neuroprotective benefit. Augmentation of the deubiquitinase activity of USP13 via gene delivery or small molecules will lead to an attractive new therapeutic strategy for PD patients with USP13 deficiency or exposed to neurotoxins. Such approaches will have a significant impact on the well-being and recovery of PD patients and reduce the socio-economic burden associated with the long-term care of patients. Since putative toxin exposure in the military is associated with the incidence of PD, the proposed work will define the interaction between environmental toxins and genes in determining the extent of a well-characterized neurological lesion (dopaminergic neuron death) by characterizing the effects of USP13 manipulation in the 6-OHDA neurotoxin PD model and the alpha-synuclein PFF neurotoxin PD model, one of the FY20 Neurotoxin Exposure Treatment Parkinson s Focus Areas.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110908
Entities
People
- Hanseok Ko
Organizations
- Johns Hopkins University
- United States Army