Development of an in-vitro model of Charcot-Marie tooth disease

Axons act as information highways that convey information from your brain to the rest of your body. Because axons are used so frequently over the course of a person s life, they are incredibly prone to degeneration. This degeneration can ultimately lead to the development of neurodegenerative disorders, such as Alzheimer s disease, Amyotrophic Lateral Sclerosis (ALS), and Charcot-Marie Tooth disease (CMT). Recently, genetic mutations in a type of enzyme responsible for maintaining protein synthesis (aminoacyl-tRNA synthetases, [ARS]) have been implicated in the development of CMT. One specific ARS (tyrosyl-tRNA synthetase [YARS]) has been linked to the development of Dominant Intermediate CMT Type C (DI-CMTC), a subset of CMT. However, although we have strong evidence to support this theory, exactly how mutated YARS (mYARS) contribute to CMT manifestation remains unclear. We manipulated mouse sensory neurons to express mYARS and observed how mYARS can lead to axon degeneration. We found that protein synthesis does appear to be affected in primary plated neurons expressing mYARS, but not in replated neurons. This led us to question what was protecting these cells from degeneration. Further examination allowed us to conclude that a crucial cell signaling pathway (mTOR signaling pathway) may be affected by mYARS, leading to decreased protein synthesis and ultimately axon degeneration.