Untangling the selectivity of alpha-synuclein pathology transmission in synucleinopathies: role of intra- and extracellular environments – SYNSELECT

Synucleinopathies encompass several neurodegenerative diseases such as Parkinson’s disease, Dementia with Lewy bodies and multiple system atrophy (MSA). These diseases are characterized by the accumulation of proteic aggregates enriched in fibrillar alpha-synuclein (asyn) in the brain of patients. Over time, asyn inclusions progress following a stereotypical pattern throughout the brain. However, the cellular populations and brain regions affected as well as the spatial pattern of progression of inclusions differ between synucleinopathies. Asyn plays a central role in synucleinopathies and its pathological forms are able to propagate in prion-like manner in the brain, underlying (at least partially) the spatial progression of asyn pathology in the brain over time. It is unclear, however, how the same protein, via the same process, affects different cellular populations and lead to different diseases with distinct clinical symptoms and histopathological lesions. Hence, the mechanisms by which the asyn pathology propagates selectively to specific cellular populations in synucleinopathies are unknown. In addition, the oligodendroglial population is specifically affected in MSA. However, oligodendrocytes do not express or express very low levels of asyn. It is thus unclear how asyn-rich glial cytoplasmic inclusions develop in MSA, and the origin of the asyn forming those aggregates is unknown.
Fibrillar asyn exist under different conformations that are able to imprint their characteristics to newly recruited asyn proteins, thus forming transmissible « strains ». In vivo, these strains trigger distinct types of inclusions and propagate differently depending on their conformation. Therefore, the existence of such strains could underlie the heterogeneity of synucleinopathies. Importantly, interactions of asyn seeds with proteins present at the plasma membrane and in the cytosol are crucial for asyn fibrils internalization and seeding in the host cell, respectively. With their different conformations, asyn strains exhibit different amino-acid stretches that are exposed to the solvent and to their proteic environment. Consequently, different strains display distinct interactomes that affect differently their prion-like propagation in specific cell types.
In addition, it is clear that the amount of asyn available in the cytoplasm of the host cell is crucial for the amplification of seeds. Hence, we hypothesize that the tropism and selectivity for specific cellular populations observed in synucleinopathies is due to strain-specific interactions with membrane and cytosolic proteins, and depends on the availability of monomeric asyn, either of endogenous or exogenous origin.
To investigate these hypotheses, we will identify strain-specific protein (membrane and cytosolic) partners involved in the selective propagation of asyn inclusions within different neuronal and oligodendroglial populations. We will then determine the exact role of protein partners in asyn pathological aggregates propagation and seeding levels in cell culture and in vivo. In addition, we will identify the origin of asyn inclusions in oligodendrocytes and determine whether particular oligodendroglial subpopulations are more susceptible to develop inclusions and why. Our work will allow the identification of protein partners that we can modulate to reduce or block the internalization and the amplification of pathological asyn seeds. Ultimately, our results will provide new approaches and potential therapeutic targets that can be adapted to patients depending on synucleinopathies, to reduce pathogenic asyn aggregates uptake, seeding and amplification in their brain and prevent harmful consequences.