• Mechanisms - Cellular and systemic propagation of protein aggregation

Parkinson’s disease, Lewy body dementia, and multiple system atrophy belong to a group of neurodegenerative diseases that are characterized by the misfolding and aggregation of a neuronally expressed protein called α-synuclein. Studies in animal models of Parkinson’s disease have shown us that, similar to prions, aggregated α-synuclein can replicate via a self-templating mechanism in neurons. Moreover, seeds of aggregated α-synuclein can be transmitted between neighboring neurons, resulting in a spread of pathology to distal brain areas over time. Our most recent findings in rodent models show that misfolded α-synuclein can spread via retrograde transport from the gut to the brain and via anterograde transport to the heart, suggesting that in some patients Parkinson’s disease may start in the gastrointestinal tract rather than in the brain. This is also supported by our epidemiological findings showing an increased risk of Parkinson’s disease after gastrointestinal infections.

• Diagnostics - Development of a diagnostic test for Alzheimer’s and Parkinson’s disease

Alzheimer’s and Parkinson’s disease are usually diagnosed relatively late during the course of the disease, at a time when severe damage to neurons has already occurred and potential treatments such as antibodies targeting amyloid-β or tau are likely to fail because too many neurons have already been irreversibly lost. Therefore, for any therapy to be effective and to protect neurons from dying, Alzheimer’s and Parkinson’s disease have to be diagnosed relatively early on during the disease course. In an effort to develop a diagnostic laboratory test for Alzheimer’s and Parkinson’s disease that can detect these diseases at an early stage, we are quantifying the amount of disease-associated amyloid-β, tau, and α-synuclein in body fluids of patients using ultrasensitive detection methods.

• Therapies - Development of a vaccine against Parkinson’s disease

Preventative treatment of infectious diseases, such as measles, polio, or influenza, by vaccination is an everyday reality that protects the lives of millions of humans. Unfortunately, no such protective vaccine currently exists against neurodegenerative diseases. Our goal is to develop a vaccine against Parkinson’s disease. In Parkinson’s disease, α-synuclein, a normal cellular protein that our neurons produce, misfolds and forms oligomers and aggregates that are damaging to neurons. Our immune system cannot mount a response to aggregated α-synuclein because it does not recognize it as something foreign and harmful. Recently, the structures of several different fibrillar aggregates of α-synuclein have been solved. Our goal is to modify the yeast protein HET-s, which can aggregate and from fibrils that are harmless to humans and can be recognized by our immune system, to mimic aggregated α-synuclein by replacing a few amino acids in HET-s with those from α-synuclein. We anticipate that vaccination with these modified HET-s fibrils will induce immunity against fibrillar forms of α-synuclein and protect from Parkinson’s disease by preventing the propagation and spreading of α-synuclein aggregates.

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