Evaluating the Role of Miro1 in Mitochondrial Quality Control in Parkinson’s Disease

Study Rationale: Growing evidence suggests that dysfunction is linked to Parkinson’s disease (PD). These structures supply cells with energy, but must be eliminated when they become damaged — a quality-control process that is impaired in PD. Miro1 is a protein that tethers mitochondria to the transport system that conveys them along nerve cell’s extended branches. This protein is normally degraded when its defective mitochondrial cargo is removed from circulation. But in the cells of people with PD, Miro1 persists. This retention of Miro1 could serve as a marker for a loss of mitochondrial quality control and potentially contribute to disease pathology.

Hypothesis: We hypothesize that retention of Miro1 is common in the cells of people with PD and that compounds that reverse this effect will promote mitochondrial quality and could be developed into a treatment for PD.

Study Design: We will expose skin cells collected from people with PD and from healthy volunteers to chemicals that will artificially induce mitochondrial damage and removal. We will then use antibodies to track the degradation of Miro1 in these cells, and assess whether a compound that reduces the levels of Miro1 will reverse the effect. We will also repeat the experiment using dopamine-producing neurons, cells that degenerate in PD, which we will derive from the skin cells of individuals with PD to see if we can observe a similar result.

Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, this study will establish Miro1 retention following mitochondrial damage as a biological hallmark of PD. Using Miro1 as a biomarker will facilitate the development of existing compounds for pharmaceutical use and subsequent clinical trials.

Next Steps for Development: We will assess what proportion of people with PD may have underlying problems in mitochondrial quality control. We would also like to determine whether compounds known to reduce the levels of Miro1 will work long term, under conditions of mild mitochondrial damage, as happens in the aging brain.