Exploring a new arm of the integrated stress response and its connection to neurodegeneration

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Charcot-Marie-Tooth disease (CMT), 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 individuals, equating to approximately 125,000 people in the United States. CMT specifically targets peripheral nerves and is characterized by weakness and wasting of the distal limb muscles leading to progressive motor impairment, sensory loss, and skeletal deformities. No curative therapy is available for CMT patients. The largest gene family implicated in CMT encodes aminoacyl-tRNA synthetases (aaRSs), which are essential enzymes catalyzing a key reaction in protein biosynthesis, namely, the charging of transfer RNAs (tRNAs) with their cognate amino acids. So far, the causality between dominant aaRS mutations and CMT has been firmly established in 5 family members (YARS1, GARS1, AARS1, HARS1, and WARS1). Despite some heterogeneities, clinical presentations of CMT patients with aaRSs mutations are highly similar, implying shared disease mechanisms. Notably, we and others have demonstrated that CMT-causing mutations do not necessarily affect the tRNA aminoacylation function of the enzymes. Instead, a potentially common neurotoxic gain of function is thought to be responsible for the neuropathy, however, its molecular basis remains largely elusive. In this proposal, we aim to test a unifying central hypothesis that dysregulation of a new arm of the Integrated Stress Response (ISR), specifically regulated by aaRSs in the nucleus, contributes to the etiology of CMT. We propose that this new arm of ISR is related to - but distinct from - the classical eIF2a phosphorylation mediated ISR pathway. Because of the different timeline of this stress response, we name it the Late Integrates Stress Response (LISR). We speculate that CMT-linked aaRSs might all be LISR-regulating aaRSs and that dysregulation of the cellular stress response system by CMT mutations results in neurodegeneration. The project will be carried out in close collaboration between Yang and Jordanova labs to explore the shared molecular mechanism by which dominant mutations in 5 different aaRSs cause CMT. Our exploration will direct future in-depth mechanistic studies and drug development programs for this severe disease. Moreover, this project will advance our understanding of basic biology through establishing a new stress response pathway specially regulated by aaRSs.