Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor and sensory neuropathy (HMSN), is the
most common form of inherited peripheral neuropathy, with an estimated prevalence of 1 in 2500 people,
equating to approximately 125,000 people in the United States. CMT affects peripheral nerves in a length-
dependent manner and is characterized by weakness and wasting of the distal limb muscles leading to
progressive motor impairment, sensory loss, and skeletal deformities. No therapy is available for CMT patients.
The largest gene family implicated in CMT encodes aminoacyl-tRNA synthetases (aaRSs), which are essential
enzymes that catalyze the first reaction in protein biosynthesis, namely, the charging of transfer RNAs (tRNAs)
with their cognate amino acids. However, understanding the connection between CMT and aaRSs is a challenge.
Because aaRSs are essential players in protein synthesis, it is believed that the CMT-causing mutations in tRNA
synthetases must affect protein synthesis in some way. Curiously, CMT-causing mutations do not necessarily
affect the aminoacylation function of the enzyme; and almost all tRNA synthetase mutations that are CMT-
associated have autosomal dominant inheritance, suggesting a gain-of-function disease mechanism. Lastly, as
protein synthesis is essential for all tissue types, the extreme tissue specificity associated with the CMT
phenotypes has complicated the biological understanding of the role of aaRSs in CMT disease. Intriguingly,
cytosolic aaRSs are also detected in the nucleus of eukaryotic cells. While the initial hypothesis was that aaRSs
function here in proofreading newly-synthesized tRNAs, later findings suggest that the nuclear-localized aaRSs
are involved in regulating a wide range of biological processes including vascular development, inflammation,
and stress responses mainly due to their distinctive abilities to interact with the transcriptional machinery.
However, the biological function of nuclear TyrRS has never been investigated in vivo in a mammalian system.
The goal of this project is to explore the physiological functions of aaRSs in the nucleus and their relationship to
CMT. Our main focus is on TyrRS, because of the established reagents and knowledge necessary for exploration
in a mammalian system and because of the recent evidence from a Drosophila model for the involvement of
nuclear TyrRS in CMT. Although the main focus is on TyrRS, we will probe commonality with other subtypes of
peripheral neuropathy as well as other neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s
disease, Huntington’s disease, and amyotrophic lateral sclerosis. This is because the nuclear function of TyrRS
is likely to be generally related to oxidative stress and to other important pathways and gene regulators that are
relevant to the neurodegenerative process independent of CMT mutations.