Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives

Multiple System Atrophy (MSA) is a severe neurodegenerative disease clinically characterized by parkinsonism, cerebellar ataxia, dysautonomia and other motor and non-motor symptoms. Although several efforts have been dedicated to understanding the causative mechanisms of the disease, MSA pathogenesis remains widely unknown. The aim of the present review is to describe the state of the art about MSA pathogenesis, with a particular focus on alpha-synuclein accumulation and mitochondrial dysfunction, and to highlight future possible perspectives in this field. In particular, this review describes the most widely investigated hypotheses explaining alpha-synuclein accumulation in oligodendrocytes, including SNCA expression, neuron-oligodendrocyte protein transfer, impaired protein degradation and alpha-synuclein spread mechanisms. Afterwards, several recent achievements in MSA research involving mitochondrial biology are described, including the role of COQ2 mutations, Coenzyme Q10 reduction, respiratory chain dysfunction and altered mitochondrial mass. Some hints are provided about alternative pathogenic mechanisms, including inflammation and impaired autophagy. Finally, all these findings are discussed from a comprehensive point of view, putative explanations are provided and new research perspectives are suggested. Overall, the present review provides a comprehensive and up-to-date overview of the mechanisms underlying MSA pathogenesis.