Celebrity plays a role in increasing public awareness of Parkinson’s disease—and drums up funding. A foundation named after actor Michael J. Fox is the largest nonprofit funder of Parkinson’s research. Another actor, Alan Alda, generated global news coverage with his recent announcement that he received a diagnosis more than three years ago. Tech titan Sergey Brin carries a version of a gene that greatly increases risk for Parkinson’s (PD), but the gene has an unwieldy name that few would otherwise recognize. These high-profile associations call attention to PD and its causes, including mutations like the one Brin carries.
A handful of gene mutations are linked to inherited PD, but they account for less than 15 percent of the one million U.S. cases and the five million worldwide. The most common of these is a mutated version of leucine-rich repeat kinase 2 (LRRK2), the one Brin carries. It is responsible for one to two percent of PD cases, but the percentage is much higher in certain groups, including those with Ashkenazi Jewish or Basque ancestry.
LRRK2 has drawn the interest of pharmaceutical companies because it is an accessible drug target. The gene encodes a namesake protein that functions as a a type of enzyme called a kinase. The LRRK2 protein attaches chemical tags called phosphates to other proteins. Like a molecular switch, these phosphate tags activate or silence LRRK2’s targets. Dozens of drugs that inhibit the activity of kinases have been approved in the last 30 years, primarily for cancer.
Now drug developers have turned to inhibiting overactive kinases in neurodegenerative and infectious diseases. The target patient population originally consisted of people with PD who also carried mutated LRRK2. In recent years, however, the Parkinson’s research community has explored whether the LRRK2 protein, which helps break down large molecules in the cell, might also play a role in nongenetic forms of the disease.
A study published July 25 in Science Translational Medicine suggests LRRK2 might indeed be a culprit in a much broader population of PD patients. “We found that the most common mutation of LRRK2 and wild-type (unmutated) LRRK2 have the same downstream pathogenic effects,” says Roberto Di Maio, a research assistant professor at the Pittsburgh Institute for Neurodegenerative Diseases (PIND) and lead author on the study.
The findings suggest many paths could lead to LRRK2 overactivity and subsequently to PD pathology. The implication: a drug roadblock of LRRK2 might halt progression of PD in people with and without the mutation. That intrigues Todd Sherer, chief executive officer of the Michael J Fox Foundation for Parkinson’s Research, which helped fund the study. Instead of developing a drug for perhaps 5 percent of the PD patient population, he says, “these data suggesting that LRRK2 plays a role in perhaps the other 95 percent…could mean a broader impact across the board.”
In their LRRK2 research Di Maio and his colleagues built on earlier results hinting that the version of the gene without any mutations might be involved in noninherited PD. The researchers took that a step further by developing a test to detect how LRRK2 interacts with other proteins. They tracked LRRK2’s activity in dopamine-producing neurons in postmortem samples from people who had PD.
Parkinson’s arises because these neurons, which are crucial to controlling movement, break down and die. With information in-hand about LRRK2’s protein interactions, Di Maio says, the team then walked step-by-step, biochemically speaking, along the paths before and after LRRK2 to detect factors that affect its activity. They found LRRK2 sits at a crossroads involving the PD-associated protein alpha-synuclein, oxygen-containing molecules tied to inflammation, and malfunctioning mitochondria, the powerhouses of the cell. As a final step in their work, Di Maio and his colleagues used rats to show inhibiting LRRK2’s hyperactivity dampens its negative effects.
It is not the first time in PD research that work with a mutated gene has led to insights affecting patients who do not carry the mutation. The story of alpha-synuclein is similar, says Rebecca Gilbert, vice president and chief scientific officer of the American Parkinson Disease Association, which also helped support the study. “There’s a whole soup of different proteins interacting in Parkinson’s, and the cascade of events may converge similarly even though there may be different mutations for different people,” she says.
Alpha-synuclein was the first gene mutation linked to hereditary PD, and it is the main component of the cell-smothering deposits called Lewy bodies that characterize the disease in the brain. Yet, as with LRRK2, most people with PD lack the alpha-synuclein mutation but still have the deposits, suggesting the protein, whether its gene is mutated or not, sits at another fateful turn on the road to the condition.
Alpha-synuclein is also tied to impairments in the mitochondria and damaging oxygen-containing molecules. These new results show mitochondrial dysfunction, alpha-synuclein overexpression and oxidative stress in general can activate LRRK2, says neurologist Timothy Greenamyre, PIND’s director and senior author on the study, all leading to similar effects.
The usual caveat with such findings is that benefits for patients are many years away. That might still be the case, but because LRRK2 had already attracted interest from pharmaceutical companies, drug development is a few steps ahead of the usual starting point. “Pharmaceutical companies don’t wait for i’s to be dotted and t’s to be crossed,” Gilbert says. “They jumped onboard with these molecules without fully understanding how LRRK2 fits into everything.”
That impatience could pay off for patients with and without the LRRK2 mutation. One big question mark, however, is LRRK2’s normal role in a cell and what happens when the protein’s activity shuts down. Like most disease-related proteins, LRRK2 has a role in maintaining health—in this case in the immune system. It works in white blood cells in a pro-inflammatory response to injury or pathogens.,
The light/dark roles of LRRK2 mean using inhibitors to dampen its effects is not necessarily a slam dunk against PD. “I think that the worry is that if you’re inhibiting LRRK2, we don’t quite know what all the side effects are going to be and if it would involve increased infection risk,” Gilbert says. Animal studies with the inhibitors hint at some off-target lung and kidney effects. Greenamyre, who is familiar with these findings, describes them as “mild” and says the changes reverse with drug withdrawal. “So far, LRRK2 inhibition appears to be acceptably safe,” he says.
Denali Therapeutics announced on August 1 positive results in an early-stage clinical trial of an LRRK2 inhibitor. This initial safety trial in healthy volunteers seems to have rung no alarm bells. Greenamyre says the next step will likely be trials with patients carrying the PD-related LRRK2 mutation. “What will be tried next is a guess,” he says, “but we believe there is a rationale for testing in the earliest stages of idiopathic or sporadic [without the mutations] PD, with a goal of slowing disease progression.”
Like other neurodegenerative conditions, the PD disease process begins before symptoms appear. Esther Sammler, a neurologist and group leader in the MRC Protein Phosphorylation and Ubiquitylation Unit at the University of Dundee, says a prodromal stage, before full-blown symptoms manifest, can begin as many as 10 years before motor symptoms are detected. Di Maio notes this presymptomatic stage might be an opportunity to test people for higher LRRK2 activity levels as a marker of PD risk, something he and his colleagues see as a next step. Another possibility, he says, is administering any successfully developed inhibitors to people at high risk for PD.
Sammler, who was not involved with the Science Translational Medicine study, is cautiously optimistic about the potential these LRRK2 findings represent. Use of the inhibitors—whether to prevent disease or slow its progression—would “only be possible if it was clear that any benefit outweighed any potential side effects,” she says, “and there is still a long way to go.”
Note: Esther Sammler's title at the University of Dundee was incorrectly specified in an earlier version of this article.