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Prion-like transmission of α-synuclein in Parkinson's disease

Objective

Protein misfolding is implicated as a pathogenetic mechanism in several neurodegenerative disorders, including Parkinson¿s disease (PD). In prion disease, the misfolded protein spreads between cells and acts as a ¿permissive template¿, causing protein in the recipient cell to misfold. In 2008 we reported that classical neuropathological changes gradually propagate from a PD patient¿s brain to a graft of healthy neurons, over one decade after surgery. These groundbreaking findings suggest that the protein ¿-synuclei may transfer between cells and propagate protein aggregation in a ¿prion-like¿ fashion in PD. This molecular disease mechanism might explain how protein aggregates gradually spread throughout the nervous system and promote progression of disease symptoms. This highly novel concept represents a hitherto poorly explored route of intercellular communication and might have far-reaching implications well beyond PD. Little is known about how various forms of ¿-synuclein are taken up; if they seed aggregation in the recipient cell; how they affect proteostasis in the recipient cells; if they are transported axonally; and, finally, whether they can cause spreading of PD-like pathology in the nervous system.
In a multidisciplinary project will now examine the molecular mechanisms underlying translocation of ¿-synuclein across a lipid membrane, from the outside to the inside of a cell; what the molecular and functional consequences are of importing ¿-synuclein; what the dynamics of ¿-synuclein transfer are in vivo; whether aggregates of misfolded ¿-synuclein can spread from one region of the nervous system to another; what genes influence the likelihood for ¿-synuclein transfer to take place; and, finally if small molecules that inhibit ¿-synuclein can be identified. Our studies will shed light on what appears to be a new principle for pathogenesis of neurodegenerative disorders and can open up avenues for new therapeutic strategies.

Call for proposal

ERC-2010-AdG_20100317
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Host institution

MAX IV Laboratory, Lund University
Address
Paradisgatan 5C
22100 Lund
Sweden
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 499 998
Principal investigator
Patrik Brundin (Prof.)
Administrative Contact
Diana Jerman (Ms.)

Beneficiaries (1)

MAX IV Laboratory, Lund University
Sweden
EU contribution
€ 2 499 998
Address
Paradisgatan 5C
22100 Lund
Activity type
Higher or Secondary Education Establishments
Principal investigator
Patrik Brundin (Prof.)
Administrative Contact
Diana Jerman (Ms.)