Mechanisms of Neurodegeneration in CMT4B3: a Complex Pediatric Neurodevelopmental Disorder

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Charcot-Marie-Tooth Disease type 4B3 (CMT4B3) is a rare, autosomal recessive hereditary axonal neuropathy, often presenting with severe regression of developmental milestones during infancy or early childhood. CMT4B3 has a wide clinical spectrum of symptoms. It ranges from an isolated demyelinating sensorimotor polyneuropathy to a complex neurodevelopmental phenotype with axonal neuropathy, cranial nerve involvement, intellectual disability and facial dysmorphism. Most children affected by CMT4B3 present with the severe phenotype. CMT4B3 is caused by mutations in the Sbf1 gene, resulting in disrupted function of the pseudo-inositol phosphatase, Myotubularin-Related Protein 5 (MTMR5). In this proposal, we focus on MTMR5, a developmentally important regulator of autophagy and endo-lysosomal trafficking, and its involvement in proper axonal homeostasis. MTMR5 is known to catalytically regulate and dictate the subcellular localization of Myotubularin- Related Protein 2 (MTMR2), an active phosphatase against phosphatidylinositol species. MTMR2 has known roles in Schwann cell homeostasis and loss of MTMR2 leads to a demyelinating neuropathy. MTMR5 was also identified as a neuron-specific suppressor of autophagy. Despite this knowledge, it is entirely unknown how disrupted function of MTMR5 leads to axonal degeneration during early childhood. Through the aims of this fellowship and using an established iPSC-derived motor neuron model of CMT4B3, I seek to clarify the biochemical role of MTMR5 in motor neurons and how loss of normal MTMR5 function results in axon degeneration early in development. In Aim 1 of this fellowship, I propose to utilize an iPSC-derived motor neuron model of CMT4B3 to understand the effects of MTMR5 loss on MTMR2, MTMR13, and phosphoinositide levels and discriminate if residual MTMR5 function causes toxicity in axons. In Aim 2, I seek to l gene expression profiling to characterize the downstream defects as a result of MTMR5 loss, which likely stem from MTMR5’s role in autophagy and endo-lysosomal trafficking. I plan to develop high-content image-based analyses to confirm expression profiling results and to create a much needed platform for drug discovery and gene therapy validation. Fully understanding the mechanisms underlying CMT4B3 is critical to the NICHD mission. Such knowledge is crucial for development and proper evaluation of therapeutic modalities that could help CMT4B3 patients. With this perspective, the proposed project is tailored to my training towards becoming a translational pediatric neurologist and scientist.