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In an international collaboration, a team from MIRCen (CEA-Jacob) studied the properties of toxic alpha-synuclein aggregates in fixed brain samples from patients, depending on their tissue origin and the type of synucleinopathy developed. These results, published in
Cells, provide a new insight into the progression of the pathology in Parkinson's disease, where different aggregates could form concomitantly and/or be modified during their propagation.
Protein misfolding and aggregation are the cause of many neurodegenerative diseases. In Parkinson's disease, one of the characteristics is the presence of neuropathological lesions known as Lewy bodies. These intracytoplasmic inclusions are rich in pathogenic aggregates of alpha-synuclein protein. Several neuropathology laboratories have shown that in addition to the substantia nigra, some structures of the central nervous system (such as the olfactory bulb or the dorsal motor nucleus of the vagus nerve) as well as the enteric nervous system1 are also affected by the pathological process in a large majority of Parkinson's patients.
As part of an international collaboration involving the team of Kelly Del Tredici and Heiko Braak2 (University of Ulm, CRB), and the French brain bank Neuro-CEB3 represented by the anatomo-pathologist Charles Duyckaerts (Department of Neuro-pathology, APHP La Pitié Salpêtrière Hospital) , the team Protein misfolding and aggregation in neurodegenerative diseases of the LMN (MIRCen) studied the properties of toxic alpha-synuclein aggregates of fixed patient samples, according to their tissue origin and the type of synucleinopathy developed (Parkinson's disease or dementia with Lewy bodies).
They characterized alpha-synuclein aggregates from tissues of different regions of the central and enteric nervous system after having amplified them in vitro by the PMCA (Protein Misfolding Cyclic Amplification) technique. This technique, originally used for the amplification of pathogenic forms of the prion protein, has been adapted here to amplify pathological aggregates of alpha-synuclein by incorporating alpha-synuclein in a healthy monomeric form. As the conformation of the pathological form is transferred to the healthy form, this technique allows the amplification of the pathological form in vitro.
The results, published in the journal Cells, reveal that alpha-synuclein aggregates do not lose their pathological ability to grow by incorporation of monomeric alpha-synuclein post-fixation from the tissue.
Structural measurements were carried out using both managed proteolysis and transmission electron microscopy. Proteolysis allows to fragment a protein using a protease, providing a specific digestion profile and a rapid analysis of its structure. Assemblies from different synucleinopathies can thus present specific proteolytic profiles, equivalent to disease-specific "bar codes". Transmission electron microscopy allows the visualization of the general morphology of protein assemblies amplified by PMCA.
These structural measurements have made it possible to show for the first time the presence of distinct alpha-synuclein aggregates (called strains) in the same individual.
This work will have to be confirmed by comparison with aggregates from non-fixed tissues from different regions to rule out a possible effect of fixation. However, these results provide a new insight into the progression of the pathology in Parkinson's disease, where different aggregates could form concomitantly and/or be modified during their propagation.
1 : The enteric nervous system, referred to as the second brain, is the part of the autonomic nervous system that controls the digestive system. Located throughout the digestive tract, it is composed of over 100 million neurons. It plays a central role in controlling functions such as regulation of digestive motor function, absorption of nutrients and control of the intestinal barrier that protects against external pathogens.
2 : Kelly Del Tredici and Heiko Braak established the scale that defines the progression of Parkinson's disease and dementia with Lewy bodies (more commonly known as Braak's stages) and linked the progression of Parkinson's disease pathological symptoms to the mode of propagation of alpha-synuclein aggregates. For more information: Stages in the development of Parkinson's disease-related pathology
3 : https://www.neuroceb.org/fr/
Propensity and Characteristics of Pathogenic αSyn Assemblies in Formalin-Fixed Human Tissue from the
Enteric Nervous System, Olfactory Bulb, and Brainstem in Cases Staged for
Parkinson’s Disease I Cells
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