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 (SkMCs) and motor neurons (MNs) during adulthood. This project focuses on the small heat shock protein HSPB3, which is upregulated in SkMCs during differentiation. HSPB3 is also found in MNs, but its physiological functions in SkMCs and MNs are largely uncharacterized. Four mutations in the HSPB3 gene were reported in Charcot-Marie-Tooth disease type 2 (CMT2) and congenital myopathy with neuropathy signs, suggesting that HSPB3 plays important functions for SkMC and MN viability. This proposal builds on extensive data revealing an unprecedented role for HSPB3 as specialized chaperone required for SkMC differentiation. Here, we aim at demonstrating if HSPB3 also promotes the differentiation of MNs, pinpointing the molecular processes that are activated by HSPB3 and deregulated by its rare variants. We hypothesize that HSPB3 dysfunction contributes to MN and muscle degeneration by impairing the regenerative capacity of the neuromuscular system. Using human induced pluripotent stem cell-derived SkMCs and MNs, we will pinpoint molecular processes that are deregulated upon HSPB3 loss or mutation, identifying HSPB3-linked pathomechanisms. Finally, we aim at identifying FDA-approved compounds that boost differentiation and axonal regeneration by upregulating HSPB3.

Potenziare l'espressione di HSPB3 per prevenire la degenerazione neuromuscolare nelle neuropatie periferiche

Tiago, T., et al., Small heat-shock protein HSPB3 promotes myogenesis by regulating the lamin B receptor. Cell Death Dis, 2021. 12(5): p. 452.

Hereditary Sensory and Motor Neuropathy

Neuropatia motoria e sensoriale ereditaria