Exploring the role of HSPB3 in chromatin remodeling for neuromuscular junction maintenance: implications for peripheral motor neuropathies

Distal hereditary motor neuropathy (dHMN2C) leads to axonal degeneration of motor neurons (MNs) and progressive muscle weakness. The neuromuscular junction (NMJ), which is the site for the transmission of signals from MNs to the skeletal muscle cells (SkMCs), is emerging as an important site of pathology. Repeated rounds of denervation and reinnervation occur during disease and failure to regenerate functional NMJs is an early event that precedes and contributes to MN loss. Thus, approaches aimed at boosting NMJ regeneration hold promise for the treatment of peripheral neuropathies. This process relies on the activation of stem cell differentiation into SkMCs and MNs during adulthood. This project is based on our recent data showing that the small heat shock protein HSPB3, whose genetic mutations are associated with dHMN2C, promotes the differentiation of SkMCs and MNs, is activated in response to axonal damage and helps the development of NMJs. We identified a number of HSPB3 partners that regulate chromatin remodeling and promote the differentiation of adult stem cells into SkMCs and MNs. Manipulating HSPB3 expression/function, acting either on its transcription or potentiating HSPB3 downstream targets could enhance the efficiency of stem cell differentiation, improving the recovery of nerve and muscle function in peripheral neuropathies. This may help to promote nerve regeneration, potentially decreasing the progression/severity of dHMN2C and other motor neuron diseases. This project aims for significant leaps in understanding HSPB3 basic functions and dysfunctions and has the potential to lead to major translational breakthroughs for the future development of novel therapies.