Lab method sheds light on how genetic mutations cause inherited Parkinson’s disease

Researchers led by the University of Dundee’s Professor Dario Alessi have developed a new method of measuring the activity of disease-causing mutations in the LRRK2 gene, a major cause of inherited Parkinson’s disease.

The team believes this research, which is published in Biochemical Journal, could help pave the way for future development of a clinical test that could facilitate evaluation of drugs to target this form of the condition.

Mutations in the LRRK2 gene are the most common cause of genetic Parkinson’s disease. The most common disease-causing mutation in this gene increases the activity of the LRRK2 protein three-fold, implying this may contribute towards the symptoms of the disease in patients. It also suggests that drugs that reduce the activity of the protein (LRRK2 inhibitors) may help treat patients with this form of inherited Parkinson’s disease.

“It is important to better understand how disruption in LRRK2 biology causes Parkinson’s disease and whether a drug that targeted the LRRK2 enzyme would offer therapeutic benefit,” said Professor Alessi, lead author on the study.

“Current drug treatments only deal with symptoms of the condition, such as tremors, but do not affect the progression of Parkinson’s disease. An important question is whether an LRRK2 therapy might have potential to slow progression of the condition, which no other current therapy is able to do.”

When the LRRK2 protein is active it stops another cellular protein called Rab10 from fulfilling its function in the body. There are many proteins in the Rab family, and a number of them have been shown to be low in number or deactivated in different forms of Parkinson’s disease.

The new method of measuring these was developed by a collaboration of researchers from Dundee, The Michael J. Fox Foundation for Parkinson’s Research, GSK and the University of Hong Kong. It analyses how much of the Rab10 protein has been deactivated – a process where phosphate groups are added to the Rab10 molecules by the LRRK2 protein – as a measure of heightened LRRK2 protein activity.

This new experimental assay is straightforward, requires only small amounts of sample material and is suitable for adapting to analyse large samples. This contrast with current mass spectrometry technology that is more complex and cumbersome and requires larger sample sizes.

While acknowledging that more work is needed, the researchers believe this breakthrough could help with future drug developments for patients with this form of Parkinson’s disease.

Professor Alessi continued, “The prediction is that elevation of LRRK2 activity leads to Parkinson’s disease, and this is now testable using our assay. The expectation is that if a sub-group of patients can be identified with elevated LRRK2 activity, these individuals might benefit most from LRRK2 inhibitors.

“I am hopeful that the new technology elaborated on in our study will greatly aide future work on defining the role that LRRK2 plays in Parkinson’s disease. I am also particularly excited about the potential of the methodology we have elaborated, especially if it could be exploited to assess LRRK2 activity in Parkinson’s patients and accelerate development and evaluation of LRRK2 drug candidates.”

The next steps for the researchers are to develop further tests to better detect and measure Rab protein deactivation and correlate elevated Rab10 deactivation with Parkinson’s disease in samples from human patients. They believe that measuring the level of Rab10 deactivation, for example in human blood samples, could allow researchers to test the efficacy of new drug candidates.

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