Investigating Mic60 as a novel gene therapy target for Parkinson's disease

摘要

ABSTRACT At present, there are no treatments that hinder or halt the inexorable progression of Parkinson disease (PD), and there is a critical need to identify treatments that can alter the course of the disease. The use of gene-transfer therapy for neurodegeneration is a burgeoning field of research that has potential for directly addressing progressive neuron loss at the cellular level. The key is to identify genetic therapies that will restore cellular health and function, thereby altering the disease course. While the specific etiology of PD remains elusive, evidence suggests that early dysfunction of mitochondrial respiration and homeostasis play a major role in PD pathogenesis. The research focus of this proposal is to evaluate the potential of the essential mitochondrial structural protein Mic60, also known as mitofilin, as an avenue to develop novel, translatable neuroprotective strategies for PD. Mic60 is a crucial component of a larger mitochondrial protein complex vital for maintaining mitochondrial architecture and function, and loss of Mic60 can detrimentally affect mitochondrial homeostasis. Mic60 function is regulated by interactions with proteins associated with PD, mitochondrial PINK1 and Parkin, which police mitochondrial health and turnover. We previously found that cellular levels of Mic60 protein are decreased in the dopamine toxicity model of PD. We also have evidence that Mic60 abundance is lower in PD patient brain. Further, we found that Mic60 overexpression protects against PD-relevant toxicants, including the mitochondrial poison rotenone. We hypothesize that the observed protective effects of Mic60 overexpression occur via stabilization of mitochondrial function. We propose to investigate the potential of Mic60 as a gene therapy candidate for PD via the following aims: In Aim 1, we will determine the ideal dose and long-term safety of viral-mediated Mic60 overexpression in vivo for delivery to the substantia nigra. In Aim 2, we will test the neuroprotective effect of Mic60 overexpression in vivo in toxicity and genetic models of PD, to evaluate the potential of Mic60 as a targeted neuroprotective gene therapy for PD. Our ultimate goal is to build on our in vitro data and evaluate Mic60 for development of a novel, neuroprotective PD treatment. As mitochondrial dysfunction is a key contributor to PD and other neurodegenerative diseases, targeting mitochondrial integrity via Mic60 to improve neuronal health may yield a therapy for both genetic and sporadic forms of PD, and possibly other neurological disorders.