Establishment and therapeutic targeting of disease signatures in patient-derived neuronal model of HINT1 neuropathy.

In 2012, our research group reported that HINT1 is associated with Charcot-Marie-Tooth neuropathy (CMT), the most common genetic disorder of the peripheral nerve. The HINT1 enzyme catalyzes the hydrolysis of purine phosphoramidases and all CMT-causing mutations result in a loss of its function. Mutations in HINT1 contribute significantly to the CMT morbidity, however, the physiological role of HINT1 in peripheral neurons and its connection to disease are unclear. In this project, I will create and characterize HINT1 patient-derived motor neurons in order to identify disease-related signatures. To this end, I will make use of transcriptomic profiling, coupled with indepth morphological characterization and functional analyses, including electrophysiological investigations. These findings will allow me to construct the HINT1 regulatory network in neuronal cells. Finally, I will attempt to pharmacologically reverse the identified disease signature(s) in the patient-derived motor neurons to provide proof-of-concept for future therapy development. As a whole, this study will decipher the fundamental role of HINT1 in neuronal homeostasis, will provide mechanistic insights on HINT1-related CMT, and will give tangible clues for designing therapeutic strategies.

Keywords:NEUROPATHY, CHARCOT-MARIE-TOOTH DISEASE

Disciplines:Genetics, Systems biology, Molecular and cell biology

Project type:Collaboration project