Ricerc@Sapienza

Duchenne muscular dystrophy (DMD) is an X-linked muscular disorder characterized by the lack of dystrophin (Dp427), a cytoskeletal protein expressed by skeletal muscles and, at lower levels, by other cells, including neurons of both central and peripheral nervous systems. Cells other than muscles may also express shorter dystrophin isoforms. Clinically, DMD is characterized by progressive muscular degeneration, which results in premature death; however, DMD patients may also exhibit neurological and autonomic disorders of various degrees. Neural alterations are established during embryonic development, suggesting a prominent role for dystrophins in nervous system differentiation. In adults, Dp427 is mainly localized at specific post-synaptic sites, where it contributes to the stabilization of neurotransmitter receptors subtypes (i.e. GABA). Oligondendrocytes and Schwann cells (SCs) also express Dp427, along with Dp140 and Dp116 isoforms, respectively. Both types of glial cells are responsible for axon myelination and intense glia-neuron cross-talk, crucial for axon growth and activity. SCs are also important for axon regeneration and maintenance of neuromuscular junctions that motor neurons (MNs) establish on skeletal muscles. To date, it is unknown whether MNs are directly affected by DMD. This project focuses on aspects of MNs survival, differentiation and activity, using adult and 5 day-old (P5) wild-type and mdx mice, a DMD animal model. At this aim, expression and localization of specific myelin proteins, as well as histological/morphometric parameters will be evaluated in the sciatic nerve. Expression and localization of GABA receptor, important in axon-SC crosstalk, will be also analyzed. This is particularly intriguing when considering that Dp427 is involved in brain GABAA receptor stabilization and activity. Comprehend whether DMD is responsible for MN functional alteration is a crucial aspect for the clinical research aiming at muscle regeneration.