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Scientific result | Highlight | Brain | Parkinson's disease | Neurodegenerative diseases
Abnormal aggregations of the alpha-synuclein protein and their propagation from one neuron to another have been shown to be primary actors in the pathophysiology of a range of neurodegenerative diseases such as Parkinson's disease, Lewy body dementia and multiple system atrophy, all grouped as a family of diseases called synucleinopathies. Although all synucleinopathies show the presence of fibrillar deposits rich in alpha-synuclein, they also show different pathological phenotypes.
That pathophysiological and clinical heterogeneity of these diseases may be explained by the presence of different "strains" of alpha-synuclein aggregates.
As a part of its continuing work(1,2,3) on the characterization of these strains, the Protein Misfolding and Aggregation in Neurodegenerative Diseases team at MIRCen decided to analyze and describe the surfaces of a range of them.
Therefore, in a recent study published in the Journal of Biological Chemistry, the researchers deployed a range of techniques to map the surfaces of various pathogenic alpha-synuclein aggregates generated in vitro and establish "fingerprints" specific to each aggregate. Their technical approach involved limited proteolysis, measurement of hydrogen-deuterium exchange at the aggregate surface, and the identification of reaction products by mass spectrometry.
The resulting high molecular resolution maps enable a better understanding of how distinct aggregates interact differently with a given proteinaceous and cellular environment. Notable structural differences and similarities were observed among the studied alpha-synuclein strains. The authors reported that the N-terminus (the "starting end" of a protein) of the alpha-synuclein in the aggregates could be used to distinguish the pathogenic functional properties of the different strains and better understand their tropism⁴ for neurons. However, the C-terminus (the "ending end" of a protein) could not be used to distinguish strains. The characteristics of both the N- and C-terminal extremities of the alpha-synuclein within the aggregates can enable the development of generic or specific ligands for diagnostic and therapeutic purposes.
The MIRCen team's work thus sets pathways to the conception and development of novel, innovative tools for the early diagnosis and treatment of synucleinopathies.
The differential solvent exposure of N-terminal residues provides 'fingerprints' of alpha-synuclein fibrillar polymorphs I Journal of Biological Chemistry
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