Is Multiple System Atrophy a Prion-like Disorder?
| Autor: | Gregor K. Wenning, Nadia Stefanova, Kurt A. Jellinger |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Protein Folding
multiple system atrophy Disease Review Pathogenesis Mice prion-like spreading Biology (General) Spectroscopy Inclusion Bodies Neurons Parkinsonism Neurodegeneration neurodegeneration Brain Neurodegenerative Diseases Parkinson Disease General Medicine Computer Science Applications Chemistry medicine.anatomical_structure alpha-Synuclein Neuroglia Astrocyte Genetically modified mouse Prions QH301-705.5 Mice Transgenic Biology Catalysis Inorganic Chemistry Atrophy α-synuclein Parkinsonian Disorders medicine Animals Humans Physical and Theoretical Chemistry Molecular Biology QD1-999 Synucleinopathies Organic Chemistry Models Theoretical medicine.disease nervous system diseases nervous system Astrocytes Macaca Lewy Bodies Neuroscience |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 10093, p 10093 (2021) International Journal of Molecular Sciences |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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