This grant builds upon the research from a prior grant: Promoting Mitochondrial Transport in Dopaminergic Neurons
Promising Outcomes of Original Grant:
Deficit in the movement of mitochondria -- powerhouses of the cell -- have been implicated in Parkinson's disease (PD) and other neurodegenerative diseases. We hypothesized that compounds that help mitochondria move down the axon -- the nerve cell's long and thin process -- might be therapeutic in PD. We evaluated over 1,000 small molecules to identify those that could improve the movement of mitochondria in brain cells and tested some of the previously identified promising compounds. As a result, we successfully identified six compounds that enhanced mitochondrial movement.
Objectives for Supplemental Investigation:
We will continue to study the compounds that enhanced the movement of mitochondria down the axons. Our immediate goal will be to determine exactly how the compounds work; specifically, we aim to determine the protein within the cell whose activity each compound targets. To accomplish this, we will target candidate proteins with molecules including interfering RNAs. Because the identified compounds have not been tested in human cells yet, we will then test their efficacy in human brain cells. The most promising candidate compounds will be tested in human dopaminergic neurons -- the cells most affected in Parkinson's -- to determine if they can promote mitochondrial movement in those cells.
Importance of This Research for the Development of a New PD Therapy:
Because brain cells rely heavily on mitochondria to supply energy to their axons, insufficient movement of mitochondria down the axon can damage the cell. Enhancing mitochondrial movement can emerge as a novel therapeutic strategy for Parkinson's disease. Identifying compounds that regulate how the mitochondria move, along with their targets, will be the starting point for developing a drug that can promote movement of mitochondria and prevent neurodegeneration in PD.