Boosting HSPB3 to prevent neuromuscular degeneration in peripheral neuropathies

Charcot-Marie-Tooth disease type 2 (CMT2) is an inherited peripheral neuropathy whose genetic mutations lead to axonal degeneration of motor neurons and progressive muscle weakness. The neuromuscular junction (NMJ), which is the site for the transmission of signals from the motor neuron to the muscle cell, is emerging as an important site of pathology in peripheral neuropathies. Repeated round of denervation and reinnervation have been reported during disease and failure to regenerate functional NMJs seems to play a prominent role in disease progression. Thus, approaches aimed at boosting NMJ regeneration hold promise for the treatment of peripheral neuropathies. This process relies on the ability of the neuromuscular system to promote the differentiation of skeletal muscle cells and motor neurons during adulthood. This project is based on our recent data showing that the small heat shock protein HSPB3, whose genetic mutations are associated with CMT2, promotes the differentiation of skeletal muscle cells by boosting the transcription of key gene pathways required for this process. Moreover, our preliminary data suggest a pro-differentiation role for HSPB3 also at the level of motor neurons. Here, we aim at demonstrating if HSPB3 promotes the differentiation of muscle cells and motor neurons, pinpointing the molecular processes that are activated by HSPB3 and deregulated by its rare variants. We also aim at demonstrating if HSPB3 promotes axonal regeneration upon damage, establishing a potential role for HSPB3 in the maintenance of neuromuscular junctions. Finally, we aim at identifying FDA-approved compounds that boost differentiation and axonal regeneration by upregulating HSPB3.