The crosstalk mediated by extracellular vesicles between skeletal muscle and motor neurons drives the Amyotrophic Lateral Sclerosis progression

Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disease affecting motor neurons in the spinal cord and motor cortex. Since its discovery, ALS has been considered as a central nervous system (CNS) disease, with its origin laying on motor neu ronal damage. However, increasing evidence is highlight ing a primary role of the skeletal muscle (SkM) in early pathogenetic events, gradually shifting ALS from a “neurocentric” paradigm to the “dying back” hypothesis. To date, ALS is recognized as a multi system dis ord e r with a complex pathogenic framework involving neuronal and non neuronal cells synergistically. In this context, extracellular vesicles (EVs), widely known for their implication in ALS by transporting pathogenic proteins and miRNAs, play a crucial role as mediators between the CNS and periphery, gaining the not only the potential as pathogenic intermediaries, but also as promising biomarkers of the disease progression. Recent findings highlighted the involvement of skeletal muscle derived EVs (SkM EVs) in mediating the transfer of neurotoxic signals, thereby contributing to neurodegeneration and reinforcing the “dying back” hypothesis. While EVs mediated intercellular communication between skeletal muscle and motor neurons is still poorly characterized, the role of EVs in ALS may extend beyond the neuromuscular junction microenvironment, also contributing to the multisystemic manifestations of ALS. Therefore, dissecting the role of EVs during the disease progression and with a different localiz ation may help in unraveling unexplored aspects of ALS pathogenesis. In this work, we characterized the molecular signature and the spatio temporal role of EVs during ALS progression by exploiting both in vitro and in vivo models, considering EVs from different sources (i.e., skeletal muscle and bloodstream, to assess the local and systemic effects on recipient cells, respectively) and from different disease stages.