Parkinson’s disease, LRRK2 and inflammation

Over the past decade geneticists have discovered a number of genes that can cause familial or inherited Parkinson’s disease. There are almost twenty known genes that can increase the risk or even cause Parkinson’s disease if they become mutated. There is much hope amongst scientists that by understanding the function of these genes new ideas about how Parkinson’s disease starts and progresses will be discovered.

There is also hope that the proteins that are made by these genes could even become therapeutic targets themselves.

One of the most common causes of inherited Parkinson’s disease is a mutation in the gene called leucine-rich repeat kinase 2 (LRRK2). Mutations in the LRRK2 gene result in changes to the LRRK2 protein and many groups around the world are working hard to deduce what the LRRK2 protein actually does.

As well as being a common cause of DNAinherited Parkinson’s disease, LRRK2 has an additional feature of interest. The feature is that LRRK2 belongs to a 518-member family of proteins called kinases. Drugs that block the activity of protein kinases have been successful for the treatment of cancer. In particular the first approved protein kinase blocking drug, Gleevac, revolutionized treatment for chronic myelogenous leukemia.

A number of drugs that block LRRK2 now exist but a pressing challenge remains. How can drugs that block LRRK2 be used if no one knows what LRRK2 actually does?

We have been exploring this question at NeuRA and our efforts so far suggest that LRRK2 may be part of the signaling pathway that regulates the inflammatory immune response to viral or bacterial infection. Intriguingly, mutations in LRRK2 can also pre-dispose to Crohn’s inflammatory bowel disease.

LRRK2 inhibitor

The first selective LRRK2 inhibitor (LRRK2-IN1)

Increased inflammation in Parkinson’s disease is not a new concept. A lot of work has shown that many markers of inflammation are increased in patients. How and why does inflammation, which everyone experiences during their lifetime, go on to cause Parkinson’s disease is hotly debated.

With funding from the Michael J Fox Foundation for Parkinson’s disease research and the Shake It Up Australia Foundation we are continuing our work to determine how LRRK2 regulates inflammation, how inflammation might lead to Parkinson’s disease and whether blocking LRRK2 with drugs will be of benefit for patients with Parkinson’s disease.

Dr Nicolas Dzamko is a Research Officer with the Halliday Group at NeuRA.

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