New research from Yale has shed light on the role of mutations in the LRRK2 gene in Parkinson’s disease.
Previous research identified an overactive protein triggered by the LRRK2 gene, which led to experimental treatments inhibiting it.
However, how exactly LRRK2 provoked the neurodegenerative disease remained elusive.
The recent study discovered that LRRK2 gene mutations can inhibit the functions of lysosomes and specialized cells called macrophages and microglia, which play crucial roles in cellular waste disposal.
Study Details and Findings
The study, published in the Proceedings of the National Academy of Sciences on July 24, reveals that mutations in the LRRK2 gene suppress the activity of lysosomes—microscopic organelles responsible for breaking down and disposing of cellular waste.
Additionally, the mutations can reduce the activity of macrophages and microglia, specialized cells that act as scavengers, clearing misfolded proteins, cell debris, dead cells, and pathogens.
In the brain, microglia protect neurons from threats posed by excessive materials.
The researchers theorize that the loss of such protective functions due to LRRK2 genetic mutations could explain the link between LRRK2 and Parkinson’s disease.
Outside the brain, the suppression of lysosomes by LRRK2 in macrophages may explain links between LRRK2 and other diseases, including leprosy and Crohn’s disease.
“LRRK2 acts like a brake on a garbage truck, and if the brake is too strong, it limits the ability of these scavenger cells to eliminate damaging material,” explains Shawn Ferguson, associate professor of cell biology and of neuroscience at Yale School of Medicine, and the study’s senior author.
Potential Implications and Future Directions
In the study, Ferguson and postdoctoral associate Narayana Yadavalli identified key downstream targets that mediate the ability of LRRK2 to suppress lysosome degradative activity.
These insights might pave the way for new therapies not only for Parkinson’s disease but also for other neurodegenerative diseases arising from lysosome dysfunction.
Ferguson suggested that the ongoing Phase 3 trial of an LRRK2 inhibitor for treating Parkinson’s—conducted by Biogen and Denali Therapeutics—may successfully restore lysosome activity in microglia.
However, he warned that caution is warranted, as weakening LRRK2’s braking ability could potentially trigger excessive cellular cleanup, damaging healthy cells.
If you care about Parkinson’s disease, please read studies about Vitamin E that may help prevent Parkinson’s, and Vitamin D could benefit people with Parkinson’s.
For more information about brain health, please see recent studies about new way to treat Parkinson’s, and results showing flavonoid-rich foods could improve survival in Parkinson’s.
The study was published in PNAS.
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