Recent findings suggest LRRK2 kinase inhibitors—a type of Parkinson’s drug now being tested in clinical trials—may benefit a broad array of patients. The research, published in the journal Neurobiology of Disease, was supported by The Michael J. Fox Foundation and built on previous research led by Tim Greenamyre, MD, PhD, at the Pittsburgh Institute for Neurodegenerative Diseases and the University of Pittsburgh.
Last year, Dr. Greenamyre transformed our understanding of LRRK2 and its role in Parkinson’s. We already knew that people with a mutation in the LRRK2 gene have increased LRRK2 protein activity in their brains and an increased risk for Parkinson’s disease. Dr. Greenamyre found that LRRK2 is overactive even in Parkinson’s patients without the genetic mutation. In this new study, he and a team of researchers delved deeper.
Deep in our brain cells, the lysosome is hard at work, clearing out used parts, debris—whatever our cells no longer need. But in people with Parkinson’s, the lysosome appears to go haywire, leaving cellular “trash” to pile up, become toxic, and damage our brain. There was some evidence to suggest that prolonged LRRK2 overactivity might contribute to this dysfunction. The team set out to prove it does by examining the effect of LRRK2 inhibitors on the lysosome.
The researchers began by looking at post-mortem brains of Parkinson’s patients without genetic mutations to understand everything that went wrong in their lysosomes. Armed with this, they knew what they were looking for in the next phase of the study. They tested a LRRK2 kinase inhibitor on a disease model and then examined the drug’s effect. They found that inhibiting LRRK2 overactivity improves the health of the lysosome, prevents the accumulation of alpha-synuclein (a hallmark of Parkinson’s), and protects brain cells from harm—all evidence that overactive LRRK2 affects the lysosome.
“Our work suggests that drugs that block LRRK2, some of which have entered clinical trials, will be useful for people with typical Parkinson’s disease,” said Dr. Greenamyre.
While results in the lab don’t always correlate to what happens in people, this study does suggest that LRRK2 kinase inhibitors could provide significant benefit to people with Parkinson’s disease, regardless of their genetic status. Denali is already testing LRRK2 kinase inhibitors in people with and without a genetic mutation. And other therapies targeting LRRK2 are in or nearing human testing.
Shake It Up have been funding LRRK2 studies since the foundation formed in 2011. It’s exciting to see this avenue of research making progress which could benefit everyone living with Parkinson’s.