Ruolo di Jab1 nel controllo dello sviluppo e rigenerazione del nervo periferico: implicazione nella patogenesi delle Neuropatie Ereditarie associate alla Distrofia Muscolare Congenita (MDC1A)

The goal of the proposal was to better dissect the molecular pathway that sustains tissue degeneration and defective regeneration in peripheral neuropathies associated to Merosin-Deficient Congenital Muscular Dystrophy type 1A (MDC1A), and in particular the role of Jab1 in this pathway. We showed that Jab1 is downstream laminin211, or Merosin, the main component of Schwann cell basal lamina encoded by the Lama2 gene and mutated in MDC1A. Mice deleted for Jab1 develop a peripheral neuropathy that is identical to the neuropathy present in Lama2 mice, and is characterized by axonal sorting defects, dysmyelination, and axonal degeneration. Loss of Jab1 also affects nerve regeneration, similarly to what is present in Lama2 mice. Finally, we displayed that axonal sorting defect and dysmyelination/axonal degeneration is the consequence of abnormal levels of p27 in Jab1KO Schwann cells, as Jab1 controls p27 . In fact, genetic downregulation of p27 in Jab1KO mice was sufficient to rescue the neuropathy. Our results amply the knowledge of the laminin211 downstream pathway that is responsible for MDC1A neuropathies and suggest that regulation of p27 levels in Schwann cells may constitute a promising therapeutical target for these neuropathies.