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Aggregated alpha-synuclein (asyn) accumulates in Parkinson’sdisease, multiple system atrophy, and dementia with Lewy bodies, collectivelyknown as synucleinopathies. The spreading pathology in these disorders appearsto involve a prion-like mechanism, whereby asyn protein assemblies are conveyedbetween brain regions and amplified by the recruitment of normal asyn inotherwise healthy cells. The underlying intercellular exchange implies at leastthree critical events: asyn membrane binding and internalization by recipientcells, interaction with intracellular α-syn, and eventual secretion ortransport into adjacent cells.
These steps were studied in experimental modelsthat recapitulate the uptake and spread of misfolded asyn following interactionwith endogenous asyn. Synucleinopathy induced by asyn fibril seeding in vitroand in vivo also provide useful preclinical platforms to test therapeutics.Proof-of-concept data will be presented showing that viral-mediated genetherapies designed to either silence asyn expression or reduce asyn protein canprevent the development of asyn pathology. Lastly, a key challenge for thetreatment of CNS disorders is the impermeability of the blood-brain-barrier tomacromolecules such as viral vectors and immunoglobulin. Non-invasive braindelivery of therapeutic biologics can be achieved using MRI-guided focusedultrasound and microbubbles, an approach that may be effective for the clinicaltreatment of synucleinopathies. |