The Relationship Between TDP-43 and Charcot-Marie-Tooth Disease

Undergraduate #64
Discipline: Biological Sciences
Subcategory: Cell and Molecular Biology

Justin A. Sherard - Delaware State University
Co-Author(s): Lauren J. Perry and Michael A. Gitcho, Delaware State University, Dover, DE

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Charcot-Marie-Tooth (CMT) disease is a neurodegenerative disorder that damages both motor and sensory nerves. Motor neuron degeneration results in muscle weakness and atrophy, and degeneration of sensory nerves results in a reduced ability to feel heat, cold, and pain. Mutations in heat-shock protein 27 (HSP27) have been shown to segregate with juvenile forms of CMT. The neuropathology of CMT shows aggregation of TDP-43 in peripheral neurons. The heterogeneous nuclear ribonucleoprotein TDP-43 is the major pathological protein in frontotemporal dementia and motor neuron disease. We are interested in investigating the role TDP-43 plays in the pathogenesis of Charcot-Marie-Tooth disease. Through immunoprecipitation and proteomics we have discovered a unique complex interaction between TDP-43, AUF1, and HSP27 that may indicate a functional role of TDP-43 in this devastating disease. We hypothesize that mutations in HSP27 will alter localization of endogenous TDP-43 in a motor neuron-like cell line (NSC34) similar to what is seen in Charcot-Marie-Tooth disease. We are in hopes that this work will give us a better understanding of the pathogenesis of Charcot-Marie-Tooth disease.

Funder Acknowledgement(s): Alzheimer’s Association New Investigator Research Grant NIRG-12-241456 ; NIH-NIA K01 1K01AG042500-01A1 ;NIH-NIGMS IDeA (P20 GM103446) INBRE Pilot Grant

Faculty Advisor: Michael Gitcho,