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Molecular "fingerprints" to better identify synucleinopathies

The term "synucleinopathy" covers a range of diseases, including Parkinson's disease, Lewy body dementia and multiple system atrophy, that involve pathological alpha-synuclein aggregations. An analysis of the properties of the different aggregate strains present in synucleinopathies has delineated the molecular bases of the diseases. The study, led by MIRCen (CEA-Jacob) researchers in partnership with the University of Louvain and Imperial College London, was published in Acta Neuropathologica.

Published on 30 April 2020

The synucleinopathies are a group of neurodegenerative diseases, all characterized by an abnormal accumulation of aggregates of a protein called alpha-synuclein. The group included such pathologies as Parkinson's disease, Lewy body dementia and multiple system atrophy.

In an international study carried out in partnership with the University of Louvain and Imperial College London, researchers from the Laboratory of Neurodegenerative Diseases (MIRCen/CEA-Jacob) showed that aggregates from any one synucleinopathy differ molecularly from those of another. The aggregates present thus differentiating, molecular "fingerprints," so to speak.

The team used an in vitro protein misfolding cyclic amplification approach on homogenates of brain tissue from deceased synucleinopathy patients to characterize the properties of alpha-synuclein aggregate strains in disease and compare them to pure in vitro alpha-synuclein assemblies.

They also studied the abilities of the different strains to provoke the characteristic symptoms of each synucleinopathy in a murine model. Some of the strains caused rapid and others slow disease progression, always with distinct inflammatory responses. Thus, in a manner similar to viral infection, the disease, its progression and the brain regions it affects are dependent on the structural properties of the alpha-synuclein aggregates.

The alpha-synuclein aggregates present in the brains of deceased patients who had Parkinson's disease, Lewy body dementia or multiple system atrophy were used to seed and template in vitro alpha-synuclein. With that approach, the team was able to show that the strains were biochemically distinct. As seen in the electron microscopy images presented here, the characteristic aggregates of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are dissimilar (black bar = 100 nanometers (one millionth of a meter)). The team's amplification approach produced sufficient alpha-synuclein aggregates to test their pathogenic properties in a murine model.
©  Luc Bousset

The study's results establish a robust molecular basis for the identification of synucleinopathies and for better pathophysiological characterizations of them. The distinct strains of alpha-synuclein aggregates would appear to correlate with the clinical presentations of their respective synucleinopathies.

The development of techniques to specifically detect the differentiating molecular fingerprint of each aggregate strain may contribute to an earlier and more precise diagnosis of disease. The work done by this international team widens the range of possibilities in the identification of therapeutic strategies for Parkinson's disease, Lewy body dementia and multiple system atrophy.

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