LRRK2 regulator ID’d as potential therapeutic target in Parkinson’s
US scientists make discovery using cell, animal models of disease
U.S. researchers have identified, as a potential therapeutic target in Parkinson’s disease, a protein that controls part of the function of LRRK2 — a protein known to be overactive in Parkinson’s, including in patients without mutations in its coding gene.
This discovery, made using cell and mouse models of the disease, could pave the way for new treatment options targeting this regulatory protein, according to the researchers, led by Yulan Xiong, PhD, an associate professor of neuroscience at the University of Connecticut Health Center.
“The significance is that we identified this key regulator that can, basically, switch on or switch off LRRK2’s GTPase function,” Xiong said in a university news story.
According to the team, new therapies developed using the study’s findings could potentially help in managing Parkinson’s disease.
The study, “CalDAG-GEFI acts as a guanine nucleotide exchange factor for LRRK2 to regulate LRRK2 function and neurodegeneration,” was published in the journal Science Advances.
Little research to date on GTPase function of LRRK2 protein
While not everyone who carries mutations in the LRRK2 gene will develop Parkinson’s, such mutations are one of the most common genetic causes of the neurodegenerative disease, which leads to a gradual loss of control over the body’s movements, as well as other symptoms.
The LRRK2 gene contains instructions for producing a protein of the same name that functions both as a kinase and as a GTPase. A kinase modifies other proteins to turn them on and off, while a GTPase binds and breaks down molecules like GTP and GDP, which act as molecular switches in certain biological processes.
Most research on LRRK2 has focused on its kinase function because it can directly control a cell’s signaling pathways. However, its GTPase function, which is associated with a region of the protein called ROC and is just as important, has not been the focus of much study.
“This is a very understudied area,” said Xiong, who collaborated with scientists at Johns Hopkins University School of Medicine in Baltimore and the Massachusetts Institute of Technology in Cambridge for this research. “There is not much work on this,” Xiong added.
GTPase function is regulated by other proteins, such as GEFs, or guanine nucleotide exchange factors, but the exact mechanisms of this regulation for LRRK2 were unclear. Until now, the researchers also did not know which GEF specifically regulates LRRK2.
Researchers investigate protein using fruit flies, mice
In this study, the researchers identified a protein called CDGI as the GEF that activates LRRK2’s GTPase function. CDGI binds to LRRK2 and helps it switch from its inactive form (GDP-bound) to its active form (GTP-bound).
The researchers looked at how CDGI interacts with LRRK2 in living organisms because these proteins are both active in signaling pathways linked to neurodegeneration. Using fruit flies, the team investigated changes in neurons, or nerve cells, in their retina — the layer inside the eye that detects light.
CDGI alone caused changes to the eye, making it look “small and rough,” according to the researchers. They found it “could be partially rescued to a bigger and smoother eye” by reducing the levels of LRRK2.
“These findings suggest that CDGI acts upstream of LRRK2 through its GEF function to regulate retinal neurodegeneration,” the researchers wrote.
In a model of Parkinson’s in which mice carry disease-causing mutations in the LRRK2 gene, a virus was used to overproduce either normal CDGI or a mutant version lacking its GEF function. The overproduction occurred in the brain’s striatum, a region important for motor control. As controls, the researchers used normal or so-called wild-type mice.
In both mutant and wild-type mice, normal CDGI caused about a 25% loss of neurons, but the mutant CDGI did not. In mice producing no LRRK2 at all, neither version of CDGI caused significant loss of neurons, confirming that CDGI acts upon LRRK2, according to the team.
Motor tests performed on these animals also suggested that “CDGI acts upstream of LRRK2 to regulate locomotor behavioral deficits,” the researchers wrote.
The university press release noted that Xiong is collaborating with a company to develop a small molecule that can cross the blood-brain barrier, a protective layer that blocks most substances from entering the brain, to deliver a potential medication that can block overactive LRRK2 in Parkinson’s.
Funding for the current research came from the National Institutes of Health, the National Science Foundation, the Parkinson’s Foundation, the William N. & Bernice E. Bumpus Foundation, the JPB Foundation, and the UConn Health Startup Fund.
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