Editors' ChoiceParkinson’s Disease

Feeling the α-synuclein strain

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Science Translational Medicine  18 Dec 2019:
Vol. 11, Issue 523, eaaz9768
DOI: 10.1126/scitranslmed.aaz9768

Abstract

α-synuclein strains may be responsible for the differing disease etiologies of the α-Synucleinopathies.

Parkinson’s Disease, multiple system atrophy, and dementia with Lewy bodies comprise a family of conditions, collectively known as the α-synucleinopathies. Despite accumulation of the same protein, α -synuclein (α-syn), within the central nervous system, these diseases have distinct clinical presentations and pathologies. It has been hypothesized that the differences could be mediated by disease-specific α-syn strains. The basis of the strain hypothesis is that one disease-associated protein conformation can template replication of more identical disease-associated forms and that strain-specific properties are encoded in these conformations.

To investigate the strain hypothesis, Lau et al. generated recombinant α-syn fibril strains with and without the inclusion of salt, which displayed distinct biochemical features. The fibrils varied in size, stability, and ability to bind an amyloid dye. The authors also compared the recombinant strains with human α-synucleinopathy samples. The different strains and human samples were inoculated into the brains of mice permissible to propagating α-syn. The mice showed strain specific disease traits, including different clinical symptoms at the onset of disease and incubation periods. When the presence of phosphorylated α-syn deposition in the brain was analyzed, distinct lesion profiles were observed with differences between the olfactory bulb, frontal cortex, parietal cortex, and hippocampus. The cell types targeted by α-syn and, within individual cells, the deposition patterns, were also influenced by strain. Overall, shorter, less stable fibrils caused earlier onset of disease with fewer regions of the brain showing deposition. These strain specific traits were reproduced over two further passages in the mice, indicating that the strain protein conformation predetermined the disease etiology and was serially propagated.

Serial propagation of differing disease phenotypes and selective regional vulnerability in mice inoculated with different α-syn fibril conformations implies that strain phenomena may be responsible for different disease etiologies. The study is not without limitations; the strain phenomena has only been demonstrated in mice that overexpress human mutant α-syn and will eventually develop disease in the absence of inoculation with a new strain. Further, the authors acknowledge that influence of the murine α-syn cannot be fully discounted. Nevertheless, understanding how different conformers attack specific brain regions and cells holds incredible potential for insight into neuronal death and dysfunction during these diseases. Furthermore, awareness of which regions are vulnerable to which strains offers an opportunity to develop ways to protect at risk neuronal populations.

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