Multiple system atrophy: advances in pathogenesis and emerging therapeutic strategies

Multiple system atrophy (MSA) is an adult onset progressive, sporadic neurodegenerative disorder. Individuals with MSA display a range of symptoms, including autonomic dysfunction, Parkinsonian features, and cerebellar impairment. Although symptomatic treatments can improve patients' quality of life, their effects are often temporary and do not alter disease progression or address its pathogenic causes. MSA patients undergo a prodromal phase that precedes the gradual onset of neuropathological changes. Therefore, understanding the early pathological events is essential for unraveling the disease's mechanisms and developing therapies to slow down its progression. Over the past five years, significant progress has been made in understanding the pathogenesis of MSA. Key findings in the epidemiology and genetics of the disease have highlighted a central role of α-synuclein (α-Syn) in the development of MSA. Numerous preclinical and clinical studies highlighted novel aspects of α-Syn aggregation, neuroinflammation, neurotrophic support, and mitochondrial dysfunction. This review covers both the traditional understanding and recent developments in MSA pathogenesis and provides an overview of related clinical trials, offering insights for future research directions in MSA.