Study Rationale:
Dopamine neurons are highly vulnerable to age-dependent increases in mitochondrial dysfunction, oxidative stress, and protein accumulation due to their high metabolic activity, low antioxidant capacity and post-mitotic nature. Failure to remove these damaged mitochondria will likely lead to a bioenergetic crisis that ultimately contributes to the onset and/or progression of Parkinson’s disease. The deubiquitinating enzyme, ubiquitin specific protease 30 (USP30) blocks mitochondrial degradation. In Parkinson’s disease, USP30 is increased in dopamine neurons, therefore, blocking USP30 may be neuroprotective by allowing damaged / dysfunctional mitochondria to be degraded.
Hypothesis:
We hypothesize that using targeted genetic technology to block USP30 will allow damaged mitochondria to be removed, and the overall pool of healthy mitochondria to increase. This will enhance dopamine neuron bioenergetics, reduce oxidative stress and promote neuronal survival.
Study Design:
This proposal will first assess the how blocking USP30 can improve mitochondrial degradation using in vitro cell culture experiments. Next, blocking USP30 as a potential treatment to halt ongoing neurodegeneration in Parkinson’s disease will be assessed using 2 different preclinical animal models of idiopathic Parkinson’s disease. USP30 expression will be reduced in the brains of rats dosed with either an environmentally relevant toxin or high levels of levels of human alpha-synuclein. Oxidative stress and dopaminergic neurodegeneration will be assessed in the brain regions of interest to assess the therapeutic benefit of blocking USP30 in idiopathic Parkinson’s disease.
Impact on Diagnosis/Treatment of Parkinson’s disease:
The proposed therapeutic is designed to halt ongoing neurodegeneration by lowering USP30 levels and increasing mitochondria degradation.
Next Steps for Development:
The results obtained from this study may lead to the development of USP30 as a therapeutic target for the treatment of Parkinson’s disease.