Scientists Discover Potential Pathway of LRRK2 Dysfunction

Researchers from Johns Hopkins University have reported on a potential route through which mutations in the LRRK2 gene — the greatest known genetic contributor to Parkinson’s disease (PD) — lead to cell death. This finding comes as much of the PD research field, including many initiatives from The Michael J. Fox Foundation, is tuned to discover more about the biology of the LRRK2 gene and its corresponding protein, a potential target of disease-modifying therapies.Gene-Mapping_5

Husband and wife Ted Dawson, MD, and Valina Dawson, PhD, led the study, partially funded by the National Institutes of Health, and recently published in Cell. MJFF did not fund this study, but has supported the work of both before.

They found that mutations in the LRRK2 gene may increase the rate at which the LRRK2 protein modifies ribosomal proteins, which are key components of protein-making machinery inside cells. This could cause the machinery to manufacture too many proteins, leading to cell death.

Experiments suggested that mutations in LRRK2 increase the rate at which it modifies two ribosomal proteins, called s11 and s15. Further tests showed that increased s15 activation was associated with cell death and abnormally high levels of all proteins. This action caused by the LRRK2 mutation may cause ribosomes (the cell’s protein-making factories) to make too much protein.

“Our results support the idea that changes in the way cells make proteins might be a common cause of Parkinson’s disease and possibly other neurodegenerative disorders,” said Dr. Ted Dawson.

He and his colleagues think that blocking excess activation of s15 ribosomal could lead to future therapies and measuring s15 could also act as a biomarker of LRRK2 activity in treatment trials.

MJFF has a LRRK2 Consortium of world-class investigators working to identify substrates of LRRK2 — the proteins that it modifies — to reveal new drug targets and biomarkers. More so toward those goals, the Foundation is gathering data and biosamples from people with and without PD with a LRRK2 mutation through the LRRK2 Cohort Consortium and the Parkinson’s Progression Markers Initiative, two large-scale clinical studies.

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