Is Multiple System Atrophy a Prion-like Disorder?

Abstract

Multiple system atrophy (MSA) is a rapidly progressive, fatal neurodegenerative disease of uncertain aetiology that belongs to the family of α-synucleinopathies. It clinically presents with parkinsonism, cerebellar, autonomic, and motor impairment in variable combinations. Pathological hallmarks are fibrillary α-synuclein (αSyn)-rich glial cytoplasmic inclusions (GCIs) mainly involving oligodendroglia and to a lesser extent neurons, inducing a multisystem neurodegeneration, glial activation, and widespread demyelinization. The neuronal αSyn pathology of MSA has molecular properties different from Lewy bodies in Parkinson’s disease (PD), both of which could serve as a pool of αSyn (prion) seeds that could initiate and drive the pathogenesis of synucleinopathies. The molecular cascade leading to the “prion-like” transfer of “strains” of aggregated αSyn contributing to the progression of the disease is poorly understood, while some presented evidence that MSA is a prion disease. However, this hypothesis is difficult to reconcile with postmortem analysis of human brains and the fact that MSA-like pathology was induced by intracerebral inoculation of human MSA brain homogenates only in homozygous mutant 53T mice, without production of disease-specific GCIs, or with replication of MSA prions in primary astrocyte cultures from transgenic mice expressing human αSyn. Whereas recent intrastriatal injection of Lewy body-derived or synthetic human αSyn fibrils induced PD-like pathology including neuronal αSyn aggregates in macaques, no such transmission of αSyn pathology in non-human primates by MSA brain lysate has been reported until now. Given the similarities between αSyn and prions, there is a considerable debate whether they should be referred to as “prions”, “prion-like”, “prionoids”, or something else. Here, the findings supporting the proposed nature of αSyn as a prion and its self-propagation through seeding as well as the transmissibility of neurodegenerative disorders are discussed. The proof of disease causation rests on the concordance of scientific evidence, none of which has provided convincing evidence for the classification of MSA as a prion disease or its human transmission until now.

A Mouse Model of Multiple System Atrophy: Bench to Bedside

“…Recently, the finding of MSA-specific a-syn strains [30,31,58] and their prion-like spreading [68][69][70] has triggered not only significant interest in this rare disease, but has opened a new avenue for preclinical in vivo modelling based on the strain-specific spreading of a-syn [71]. However, typical GCIs, which are widely spread in the human MSA brain, are not readily seen in the rodent brain after intracerebral inoculation of a-syn fibrils.…”

Heterogeneity of Multiple System Atrophy: An Update

“…In addition to "mixed" MSA with a combination of both phenotypes, there are several clinico-pathological variants [1,7,8], which will be critically reviewed here in order to improve diagnostic accuracy of this disorder that shows overlap with other extrapyramidal disorders. The underlying pathogenic mechanisms are still not well understood, but there is evidence for the notion that a "prion-like" spreading of disease-specific αSyn strains is involved in the pathogenic cascade [9,10]. Together with oxidative stress, proteasomal and mitochondrial dysfunctions, myelin dysregulation, the redistribution of the oligodendrocyte-specific protein p25α, neuroinflammation, impaired neurotrophic factors, and energy failure, it is involved in the complex pathogenic process finally leading to a specific multisystem degeneration in this oligodendroglio-neuronal proteinopathy [1,9,[11][12][13][14][15][16] (Figure 1).…”

“…The underlying pathogenic mechanisms are still not well understood, but there is evidence for the notion that a "prion-like" spreading of disease-specific αSyn strains is involved in the pathogenic cascade [9,10]. Together with oxidative stress, proteasomal and mitochondrial dysfunctions, myelin dysregulation, the redistribution of the oligodendrocyte-specific protein p25α, neuroinflammation, impaired neurotrophic factors, and energy failure, it is involved in the complex pathogenic process finally leading to a specific multisystem degeneration in this oligodendroglio-neuronal proteinopathy [1,9,[11][12][13][14][15][16] (Figure 1). tion to "mixed" MSA with a combination of both phenotypes, there are several clinico-pathological variants [1,7,8], which will be critically reviewed here in order to improve diagnostic accuracy of this disorder that shows overlap with other extrapyramidal disorders.…”

MhcII Regulates Transmission of α-Synuclein-Seeded Pathology in Mice

“…Synucleinopathies are a spectrum of neurodegenerative diseases characterized by the aggregation of the naturally soluble α-synuclein (α-syn) protein and its propagation within the brain [ 1 ]. Recent evidence shows that α-syn proteinopathy can be induced in the periphery and spread into the brain via a prion-like transmission process [ 2 , 3 , 4 ]. How such proteinopathy can be transmitted from the periphery to the brain remains under investigation.…”