Selectivity of alpha-synuclein pathology transmission in synucleinopathies: role of alpha-synuclein strains and their interactomes?
Résumé
Aims
In synucleinopathies alpha-synuclein (asyn) aggregates and spreads in the brain in a prion-like manner, affecting different cells populations and brain regions depending on the disease, and leading to distinct histopathological and clinical features. However the mechanisms underlying the selective vulnerability and tropism for different cell populations remain unknown. We know that αsyn can misfold and acquire different conformations, generating polymorphs / strains that can propagate. These strains can be produced in vitro but also amplified from human brains with synucleinopathies. We have previously demonstrated that different strains (produced in vitro or amplified from post-mortem brain tissue) are able to propagate differently in cell culture and in rodents brains. We now hypothesize that the selectivity of pathological asyn for specific cellular populations relies notably on strain-specific interactions with intracellular and membrane proteins.
Methods
Using proteomic approaches, we investigate strain-specific interactomes in different cellular populations.
Results
We have identified specific interactomes for different asyn strains as well as common interactors for all strains.
Conclusions
Our aim is to determine which interactions play key roles in strain-specific and selective propagation of pathological αsyn, and to select potential interactors to target in order to prevent or limit the transmission/amplification of αsyn strains.