LRRK2 mutations may curb certain immune cells’ ability to clear waste
Mutations might contribute to Parkinson's by reducing lysosome activity: study
Mutations in the LRRK2 gene might contribute to Parkinson’s disease by suppressing the activity of lysosomes, the cell compartments responsible for clearing misfolded proteins and other cellular waste, according to a recent study.
In cell culture experiments, Parkinson’s-associated LRRK2 mutations were linked to reduced lysosome activity in microglia and macrophages, two types of immune cells that play a key role in clearing cellular debris, whereas genetic deletion of the gene had the opposite effect.
Altogether, LRRK2 mutations might mean that the body’s cells are not as good at clearing waste, including the misfolded version of the alpha-synuclein protein that toxically accumulates in Parkinson’s.
“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,” Shawn Ferguson, PhD, associate professor of cell biology and neuroscience at Yale School of Medicine and the study’s senior author, said in a university press release.
Findings support development of LRRK2-targeted therapies for Parkinson’s
Scientists believe the findings support the further development of LRRK2-targeted therapeutics for Parkinson’s and other diseases arising from lysosome dysfunction.
The study was published in PNAS and titled “LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition.”
Mutations in the LRRK2 gene are the most common genetic cause of familial Parkinson’s disease in addition to being a risk factor for sporadic, or non-familial, Parkinson’s.
This gene encodes production of the leucine-rich repeat kinase 2, or LRRK2, enzyme. Parkinson’s-causing mutations generally lead to the production of excessive or overactive LRRK2 enzyme.
It is not known exactly how changes in LRRK2 function might underlie Parkinson’s, but research indicates that the protein is involved in supporting the health of lysosomes.
These waste-clearing organelles are critical for maintaining normal cellular activities, and their dysfunction has been implicated in a range of diseases including Parkinson’s.
The relationship between LRRK2 and lysosomes might be particularly important in microglia and macrophages, given the fact that these cells are key for clearing potentially harmful molecules in the cellular environment, according to the researchers. While macrophages play this role throughout the body, the closely-related microglia are brain-resident.
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.
Researchers examined lysosome activity in cells lacking LRRK enzyme activity
To further investigate, the researchers examined lysosome activity in human-derived macrophages that were lacking the LRRK2 gene or in cells where the LRRK2 protein was pharmacologically inhibited.
They found that a lack of LRRK2 enzyme activity in either case was linked to higher proteolytic activities in lysosomes, meaning they were more effectively breaking down proteins. The researchers also observed a corresponding increase in various hydrolases, the enzymes in lysosomes that mediate their ability to break down different types of waste.
On the other hand, macrophages expressing a Parkinson’s-associated LRRK2 mutation believed to increase LRRK2 enzyme activity had lysosomes with reduced proteolytic activity.
LRRK2 inhibition led to increased activity of genes responsible for producing lysosomal proteins in macrophages, whereas Parkinson’s LRRK2 mutations led to reductions in such gene activity.
The protein’s ability to regulate gene activity important for lysosome function appeared to come from its regulation of MiT-TFE, a group of proteins called transcription factors that influence the activity of other genes.
Similar to findings in macrophages, LRRK2 inhibition was associated with increased lysosomal activity in microglia.
While the scientists focused here on macrophages and microglia, the effect of LRRK2 mutations on lysosome function is likely to have significant impacts in other cell types, including the dopamine-producing nerve cells that are lost in Parkinson’s, the researchers noted.
Experimental LRRK2-inhibiting therapy BIIB122 currently in Phase 2 trial
Overall, the finding that LRRK can suppress lysosomes via regulation of MiT-TFE “opens up opportunities to define more detailed molecular mechanisms and to determine the contributions of such regulation to both normal cell biology and to Parkinson’s disease risk,” the scientists wrote.
The team believes the findings offer support for current therapeutic approaches to inhibit LRRK2 for Parkinson’s. One such experimental therapy is Biogen’s BIIB122, which is currently being tested in Parkinson’s patients in a Phase 2 trial (NCT05348785).
However, too much inhibition of LRRK2 could have negative consequences. In animal models, LRRK2 inhibition caused lysosome abnormalities in the kidneys and lungs.
Whether that “will limit the feasibility of long-term LRRK2 inhibition in humans” will be answered in ongoing clinical trials, the team noted.
Beyond Parkinson’s, the findings might also help explain observed links between LRRK2 and other diseases outside the brain, such as leprosy and Crohn’s disease.
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