Pathogenesis of Multiple System Atrophy - Recent Developments

Abstract

Multiple System Atrophy (MSA) is a rare adult-onset neurodegenerative disorder of uncertain etiology, clinically manifesting with parkinsonism, cerebellar impairment, autonomic dysfunction and pyramidal signs. The pathological process affects striatonigral, olivopontocerebellar, and autonomic nervous systems. The major clinical variants correlate to the morphologic phenotypes of striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C). Pathologically, MSA is characterized by Glial Cytoplasmic Inclusions (GCIs) and Neuronal Inclusions (NIs) containing abnormal filamentous α-synuclein that involve many areas of the nervous system. In addition to extopic deposition of modified α-synuclein in oligodendroglia and neurons, oxidative stress, proteasomal and mitochondrial dysfunction, dysregulation of myelin lipids, demyelination, neuroinflammation, and energy failure contribute to the pathogenesis of system-specific neurodegeneration in this unique proteinopathy.