Investigating the Mechanosensory System in Friedreich’s Ataxia using Stem Cell Models

This project will use induced pluripotent stem cells to generate the specialized nerve cells that are defective in FA and investigate how they respond to mechanical stimuli to understand how they contribute to the pathology in FA. Mechanosensation plays a crucial role in regulating daily functions such as balance, mobility, bladder control, and digestion. The mechanosensory system is comprised of different nerve cells that are located within the spinal cord, which include (1) proprioceptor cells, which detect movement, balance, muscle pressure, and tension, and (2) low threshold mechanoreceptors (LTMRs), which detect touch, vibration, and internal organ sensation. The degeneration of this mechanosensory system is a characteristic hallmark of Friedreich’s Ataxia (FA), with the degeneration of proprioceptor cells leading to impaired proprioception, causing difficulties in maintaining balance and coordinating movements. Additionally, FA patients may experience sensory abnormalities related to the degeneration of LTMR cells, such as altered touch perception, reduced ability to sense vibrations, and impaired bladder and bowel function; however, the role of LTMR cells in the progression of FA remains uncharacterized. Additionally, it is not clear why these mechanosensory nerve cells are specifically affected by the low frataxin levels in FA compared to other cell types. To better understand what is happening to the mechanosensory system in FA, Dr. Hulme will use patient derived-induced pluripotent stem cells (iPSCs) (which can be transformed into any cell type in the body) to generate the proprioceptor and LTMR nerve cells. By studying these iPSC-derived nerve cells, Dr. Hulme will investigate the molecular and functional aspects of these mechanosensory nerve cells and examine how these cells respond to types of mechanical stimuli such as touch and stretch. Providing a platform to unravel the connection between FA symptoms and the malfunctioning mechanosensory system. Additionally, this project also aims to test compounds on these cells and assess their effectiveness in restoring normal mechanosensory function or protecting against degeneration. This research will further discover the contribution and roles of mechanosensory nerves in FA and will ultimately assist in the development of FA therapies that target specific cell types. It will also provide a novel platform to screen candidate FA therapies. This research hopes to be used to develop potential interventions to alleviate symptoms and improve the quality of life for individuals affected by FA.