Approximately 4 million people worldwide currently suffer from Parkinson's disease (PD), and this number is only expected to increase. The most frequent genetic causes of the illness are mutations in the gene responsible for controlling the production of protein LRRK2, which includes two enzymes: a kinase and a GTPase. Because this kinase is at the root of neuronal problems, kinase inhibitors have already been clinically tested. However, these inhibitors eventually cause lung and kidney problems, making it imperative for scientists to seek alternative solutions.

An international group of researchers has unraveled the workings of an essential mechanism in 'Parkinson's protein' LRRK2. Their study demonstrates a direct link between the protein's 'dimerization' - two copies that are bound together -and mutations that lead to Parkinson's disease. This process could eventually lead to a promising therapy route. This research has been published in the leading academic journal Nature Communications.

Parkinson's protein comes in a single or doubled state. Researchers sought a better understanding of LRRK2's complex structure. It is already known that the kinase portion of the protein is active in the protein's 'dimeric' or 'double' state, which involves two identical copies of the protein bound together. Using this information as a starting point, the team investigated how this binding is established. To do so, the scientists observed similar proteins occurring in certain bacteria.

They show that oligomerization of a homologous bacterial Roco protein depends on the nucleotide load. The protein is mainly dimeric in the nucleotide-free and GDP-bound states, while it forms monomers upon GTP binding, leading to a monomer-dimer cycle during GTP hydrolysis. An analogue of a PD associated mutation stabilizes the dimer and decreases the GTPase activity.

Senior author said: "The GTPase enzyme, a component of LRRK2, regulates the state of the entire protein. In doing so, it determines whether a LRRK2 protein is in its inactive 'single' state, or its active 'double' state. In addition, we saw a clear link between the protein dimerization and genetic mutations in Parkinson's disease. As a result, this regulation process constitutes an attractive new target for future drug development."
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http://www.vib.be/en/news/Pages/Newly-described-process-in-Parkinson%E2%80%99s-protein-as-a-potential-new-therapy-route.aspx

https://www.nature.com/articles/s41467-017-01103-4