Evaluating Mitochondrial Transport in CHCHD10S59L-Mediated ALS-FTD

Abstract

Amyotrophic lateral sclerosis with frontotemporal dementia (ALS-FTD) is a lethal age-progressive disease characterized by motor and behavioral deficits, as well as personality changes. With no effective treatments and its complex clinical spectrum, there is a great need to further elucidate the pathogenesis of ALS-FTD. A single amino acid substitution mutation in the mitochondrial protein, coil-coiled-helix-coil-coiled-helix domain containing 10 (CHCHD10S59L), leads to familial ALS-FTD. Previously, we demonstrated that the CHCHD10S59L mutation resulted in mitochondrial dysfunction in Drosophila and various cell culture models. Axonal mitochondrial transport ensures that mitochondria are transported to high-energy demanding sites, such as synapses, to help aid in synaptic communication. Reduced mitochondrial transport is demonstrated in various neurodegenerative disease models including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and other disease mutations of ALS. This suggests that maintaining proper mitochondrial transport is paramount to the health of neurons. Since it is known that the ALS-FTD causing mutation CHCHD10S59L leads to mitochondrial dysfunction, and abnormal mitochondrial transport is present in other neurodegenerative disorders, the goal of this study was to determine if abnormal mitochondrial transport was also present in CHCHD10S59L-mediated ALS-FTD. Using a Drosophila larval model system and multiple different expression patterns, it was determined that male larvae with 1 copy of the S59L mutation displayed significantly less anterograde mitochondrial movement in the transport parameters flux, distance, and run length. However, there was no widespread reduction in mitochondrial motility as expected and the majority of the data was inconsistent between the different expression lines. This could suggest that larva have a greater need for mitochondrial motility to support their development, especially the growth of adult specific neurons, and any motility defects that could be present from the S59L mutation, are outweighed by the larva’s need for increased mitochondrial motility to support that growth and development. Repeating this project in an adult Drosophila system, as well as utilizing an in vitro model would help to further elucidate the role, if any, that mitochondrial transport has on the pathogenesis of CHCHD10S59L-mediated ALS-FTD.