Multiple system atrophy: pathogenic mechanisms and biomarkers

Abstract

Multiple system atrophy (MSA) is a unique proteinopathy that differs from other α-synucleinopathies since the pathological process resulting from accumulation of aberrant α-synuclein (αSyn) involves the oligodendroglia rather than neurons, although both pathologies affect multiple parts of the brain, spinal cord, autonomic and peripheral nervous system. Both the etiology and pathogenesis of MSA are unknown, although animal models have provided insight into the basic molecular changes of this disorder. Accumulation of aberrant αSyn in oligodendroglial cells and preceded by relocation of p25α protein from myelin to oligodendroglia results in the formation of insoluble glial cytoplasmic inclusions that cause cell dysfunction and demise. These changes are associated with proteasomal, mitochondrial and lipid transport dysfunction, oxidative stress, reduced trophic transport, neuroinflammation and other noxious factors. Their complex 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 associated with neuronal pathways result in a multi-system involvement. No reliable biomarkers are currently available for the clinical diagnosis and prognosis of MSA. 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.

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

“…In addition, both TPPP/p25 [15] and SYN [60] were detected in the cerebrospinal fluid of human patients. Extracellular transmission of these proteins, therefore, is a plausible explanation for the development of pathological inclusions in the case of Parkinson's disease and multiple system atrophy [16,61,62].…”

“…Targeting by competitors/foldamers should impede/destruct the small soluble assemblies, the fatal species in the development of synucleinopathies. The pathological complex has been suggested functioning as an initiator in the etiology of Parkinson's disease and multiple system atrophy [16][17][18]61,62]. We explored the challenges associated with targeting chameleon proteins using the TPPP/p25-SYN complex as a case study.…”

The neuropathology of the adult cerebellum

“…8.2B). The immunoreactivity of gci with antibodies to a-synuclein has prompted the assignment of MSA to the “synucleinopathies,” and the disease may involve a prion-like spread of a-synuclein aggregates (Jellinger and Wenning, 2016). Protein aggregation in gci involves multiple other proteins, and a-synuclein constitutes only 11.7% of the total protein (McCormack et al, 2016).…”

The Retina in Multiple System Atrophy: Systematic Review and Meta-Analysis

“…Because current candidate biomarkers for MSA from blood, cerebrospinal fluid, and brain or cardiac imaging are neither sensitive nor specific or insufficiently explored (7), OCT-detected retinal abnormalities could emerge as a useful biomarker of disease progression (8). In this article, we briefly review the normal anatomy of the retina and perform a literature review of retinal abnormalities as a biomarker in patients with MSA and a meta-analysis on the main results of OCT studies in patients with MSA.…”