Understanding the Two Different Forms of Alpha-Synuclein Aggregates in Parkinson’s Disease Patients and the Effects of Familial Risk Mutations and Investigational Drugs: Insights from Viennese Researchers Published in “PNAS”.

2023-04-18 18:00:00

Patients with Parkinson’s disease and Lewy body dementia usually have clumps (aggregates) of the protein “alpha-synuclein” in their brain.

There are two different forms of these aggregates, report Viennese researchers in the journal “PNAS”. They also found that familial risk mutations and an investigational drug altered alpha-synuclein junctions in opposite ways.

Characteristic feature

Alpha-synuclein is one of the most common proteins in the human brain and a component of nerve cells. It is mainly found in the synapses, where signals are passed from one nerve cell to the next. There, alpha-synuclein is probably involved in the release of messenger substances. Clumps of the protein are a characteristic feature of both neurodegenerative diseases. Certain genetic changes to the protein increase the risk of Parkinson’s in affected families.

A team led by Robert Konrat from the Max Perutz Labs in Vienna investigated what these clumps look like. Alpha-synuclein is one of the “intrinsically disordered proteins” and therefore has no fixed structure. Two different forms were found – one with a “ring-like structure that can form a kind of pore in the membrane of the cells”, which makes the membrane permeable and allows substances to flow in and out unhindered. Second, the researchers saw “elongated aggregates that are twisted and twisted.” They detach from the membrane, attract more synuclein molecules, and give rise to larger and larger clumps. Currently in clinical trials is the pharmaceutical UCB0599, which eliminated such aggregates in animal studies.