Sergey Brin, the co-founder of Google, has an increased risk of developing Parkinson’s disease because he harbors a mutation in a protein called Leucine-rich repeat kinase 2, or LRRK2. The protein is viewed as a promising drug target to treat Parkinson’s, a progressive neurological disorder, but it’s not possible to track LRRK2 activity in the brain, making the search for targeted therapies against the disease challenging. In a new study, researchers now provide evidence for a way to measure LRRK2 activity—and a new compound that can block the damaging effects of the protein in rodent neurons.
“This study is important because the authors showed that specific mutations in LRRK2 activate it and cause damage to nerve cells. This finding can now provide opportunities to monitor the effects of LRRK2 inhibitors in cells and animals,” says Howard Federoff, executive dean of Georgetown University’s School of Medicine in Washington, DC, who was not involved in the study.
Parkinson’s disease affects approximately 10 million people worldwide by impairing motor functioning caused by the death of dopamine-secreting neurons in the brain. Mutations in LRRK2 are the most common cause of familial Parkinson’s disease, accounting for about 2% of all patients with Parkinson’s. Specific mutations in LRRK2 increase its enzyme activity. A 2006 study in Nature Neuroscience revealed that mutations affecting LRRK2 activity can damage mouse nerve cells grown in culture. A 2010 study published in Nature Medicine showed that inhibiting LRRK2 can prevent some of the symptoms of Parkinson’s disease in a mouse model. However, an understanding of how LRRK2 causes neuronal damage remained elusive.
Today, reporting in Science Translational Medicine, a collaborative team led by neurologist Haitao Zhu and chemist Don Kirkpatrick at biotech powerhouse Genentech, based in South San Francisco, California, identified several abnormalities in mutated LRRK2 at a site of the protein known as serine 1292 that make it more active—and thereby more toxic to neurons. The identification of serine 1292 allowed the researchers to develop an antibody that could bind to the protein, allowing them to build an assay that measured the amount and activity of LRRK2.
Subsequently, the researchers found that the amount of LRRK2 with this serine 1292 modification—specifically, the addition of a molecule known as a phosphate group—was ten times higher in cells taken from the brains of mice genetically engineered to carry mutated LRRK2 compared to that seen in normal mice.
The scientists also developed a molecular screening approach to test hundreds of potential LRRK2 inhibitors. In the end, they identified one such compound, G1023, which completely removed the bound phosphate group in mutated LRRK2. G1023 protected embryonic neurons taken from mice with the LRRK2 mutation, returning the growth rate of these cells to the same level as that seen in cells taken from healthy mice.
“The serine 1292 site is highly conserved through evolution from worms to humans, suggesting that it is very important for the function of LRRK2 and can be used as a starting point in drug discovery to prioritize compounds that are selective, potent, and brain-penetrable,” says Zhu.
“We still don’t know if this inhibitor molecule will be protective in an animal, but now they are well prepared to do these studies,” says Federoff. Zhu and Kirkpatrick agree that the next step, now that they have an inhibitor, is to test its efficacy in an animal model, as a necessary first step to evaluate whether to ultimately go forward with a human clinical trial.