2023-04-18 12:35:00
People 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. They also found that familial risk mutations and an investigational drug alter alpha-synuclein junctions in opposite ways. The study was published in the journal “PNAS”.
Alpha-synuclein is one of the most common proteins in the human brain and a normal 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 (neurotransmitters).
Lumps as a characteristic feature of the disease
In two neurodegenerative diseases, namely Parkinson’s disease and Lewy body dementia, aggregates of alpha-synuclein are a hallmark of the disease. It is unclear whether they actually cause problems or are just a side effect of the diseases. However, there are certain mutations (gene changes) in alpha-synuclein that increase the risk of Parkinson’s disease in affected families. A drug (UCB0599) that eliminated such alpha-synuclein aggregates in animal studies is currently in clinical trials.
Structural diversity of alpha-synuclein aggregates
A team led by Robert Konrat from the Max Perutz Labs in Vienna investigated what alpha-synuclein aggregates look like. It belongs to the “intrinsically disordered proteins” and therefore has no fixed structure, Konrat said in an interview with the APA: “We therefore first had to optimize the methods in order to record its structural diversity.” This has now been achieved for the first time with a “medically very relevant protein”.
“We found two different forms of aggregates,” says Konrat: “One of them has a ring-like structure that can form a kind of pore in the cell membrane.” This means that the membrane becomes permeable and a wide variety of substances can flow in and out unhindered. “Of course, this poses a problem for the cells,” he explained. Second, the researchers saw “elongated aggregates that are slightly twisted and twisted.” They detach from the membrane, attract more synuclein molecules from the membranes and are the germ for ever larger aggregates.
Using their high-resolution structural model of alpha-synuclein aggregates, the researchers were also able to identify where the two known familial risk mutations for Parkinson’s disease actually change the protein. “This happens exactly in the intermediate area where two synuclein molecules meet,” said Konrat: “The mutations therefore lead to the points of contact changing and thus also the aggregate structure.”
The pharmaceutical “UCB0599”, which is being tested in “phase II” clinical studies in human patients, also acts exactly at these points of contact, but in exactly the opposite way than the mutations. The contacts are becoming fewer instead of more. This could explain why this substance breaks down alpha-synuclein aggregates.
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