Recent advances in multiple system atrophy

Abstract

Multiple system atrophy (MSA) is a fatal orphan neurodegenerative disorder that manifests with autonomic, parkinsonian, cerebellar, and pyramidal features. It is characterized by the accumulation of misfolded α-synuclein (αSyn) in oligodendroglia and neurons, affecting multiple parts of the central, autonomic and perípheral system. Both the etiology and pathogenesis of MSA are unknown, although a genetic component has been proposed. Accumulation of aberrant αSyn in oligodendrocytes, preceded by relocation of p25α protein from myelin into oligodendroglia, results in the formation of insoluble glial cytoplasmic inclusions (GCIs). These changes are associated with proteasomal, mitochondrial and lipid transport dysfunction, oxidative stress, reduced trophic transport, neuroinflammation and other noxious factors. Their interaction induces dysfunction of the oligodendroglial-myelin-axon-neuron complex, resulting in the system-specific pattern of neurodegeneration characterizing MSA as a synucleinopathy with oligodendroglio-neuronopathy. Propagation of modified toxic αSyn species from neurons to oligodendroglia by "prion-like" transfer and its spreading to associate neuronal pathways result in multi-system involvement. No reliable biomarkers are currently available for the clinical diagnosis and prognosis of MSA and neither effective neuroprotective nor disease-modifying therapies of MSA are available, although novel treatment strategies targeting αSyn are under discussion. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes to develop reliable diagnostic biomarkers and to deliver targets for effective treatment of this hitherto incurable disorder is urgently needed.