Presenting Author:

Éanna Ryan

Principal Investigator:

Teepu Siddique, M.D.

Department:

Neurology, Ken and Ruth Davee Department

Keywords:

ALS, Mouse, CHCHD10

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B113 - Basic Science

Characterization of transgenic mice expressing ALS-associated CHCHD10-R15L

Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 10 (CHCHD10) is a nuclear gene that encodes for a protein of unknown function that is enriched in mitochondria. We, and others, have identified mutations in CHCHD10 in a variety of degenerative diseases including, but not limited to, amyotrophic lateral sclerosis (ALS) and mitochondrial myopathy. Using the approach of whole exome sequencing, we identified an R15L missense mutation in CHCHD10 in individuals from a large, multi-generational familial ALS pedigree. The mutation was subsequently identified in four additional families. In an effort to better understand the pathogenic mechanism of this mutation, we engineered transgenic mouse models expressing either the wild type or mutant variants of human CHCHD10. Pathological, biochemical and behavioral characterization of these mouse lines has provided insight into the possible disease processes involved. Severe axonal pathology is apparent in a diverse range of neurons throughout the central nervous system in CHCHD10-R15L transgenic mice. The pathology is first evident around 60 days of age, yet the mice survive well beyond this. Although the CHCHD10-R15L transgenic mice have an abbreviated lifespan compared to controls, they perform comparably in motor behavior tasks up to the point of death. The cause of death is currently under investigation. Preliminary biochemical studies indicate that this mutation does not impair targeting of CHCHD10 protein to mitochondria or the efficiency of action of the electron transport chain. This novel mouse model supports the hypothesis that the R15L mutation impacts upon normal central nervous system functioning, as evident by the presence of axonal pathology. The mechanism by which the pathology manifests a behavioral deficit requires further investigation.