Blocking an overactive Parkinson’s enzyme restores dopamine release in middle-aged mice and fails in old ones

In Short. In mutant mice, a drug that blocks LRRK2, an enzyme overactive in some inherited Parkinson’s, increased dopamine release at middle age but did not restore it in old age. The unreviewed results suggest such treatment may need to start early.

PARKINSON’S DISEASE destroys the brain cells that make dopamine, a chemical that nerve cells use to signal to one another. These cells send long fibers into the striatum, a region deep in the brain that helps control movement, and release dopamine there. By the time a person is diagnosed, at around 65, about 70% of those fibers may already be gone, according to the introduction of a new study from McGill University, in Montreal. That is why researchers want to know when dopamine release first starts to fail, and whether a drug given before then could prevent it.

One candidate target is an enzyme called LRRK2. Enzymes of this kind attach small chemical tags to other proteins, which changes how those proteins behave. Some inherited forms of Parkinson’s are caused by mutations that make LRRK2 overactive, among them one called G2019S. A drug that blocks this tagging activity is known as a kinase inhibitor, and one has already been tested in a large trial in people.

The new work, from the laboratory of Austen Milnerwood, was posted on October 16th on bioRxiv, a website for papers that have not yet been peer reviewed (Gentle et al.). The team studied mice bred to carry G2019S, along with a second line carrying a rarer mutation, in a gene called VPS35, that also makes LRRK2 overactive. To measure dopamine release, they delivered a gene for a sensor called dLight into the striatum, which makes the tissue glow when dopamine reaches it. Weeks later they cut thin slices of the brain, stimulated them with small electrical pulses and filmed the glow. Release was therefore measured in slices of tissue rather than in living animals, and the study did not test movement or behavior. The drug was MLi-2, a research compound that is not a medicine, and it was given for about two hours rather than as long-term treatment.

The authors matched mice aged 3, 6 and 25 months to people of about 20, 30 to 40, and 65 years. In G2019S mice, release was normal at 3 months. By 6 months it was lower in males, while the fall in females was not yet statistically significant. At 25 months, release was 30 to 50% below that of normal mice in both sexes and in both mutant lines.

At 6 months, the age at which the deficit first appeared, two hours of MLi-2 increased dopamine release in slices from mutant males. In females, comparing treated and untreated slices taken from the same animal also showed a significant rise, and the authors describe the drug as restoring release at this age. At 25 months the drug did not restore release, even though the mice received it by injection two hours before the slices were cut and the slices were kept in it during recording. The authors suggest that by old age changes may have built up that blocking the enzyme can no longer reverse, and they write that long-term inhibition might still protect older animals from further decline.

An independent group at the universities of Ferrara and Padova, in Italy, reported a different picture in 2017 (Longo et al.). They measured dopamine in living G2019S mice by microdialysis, which draws fluid from the brain through a fine probe. In mice aged 12 months or older, they found dopamine levels similar to those of normal mice rather than lower, and a LRRK2 inhibitor did not change release. The two studies used different methods, different ages and different inhibitors.

Results in people have so far been discouraging. In a trial called LUMA, Biogen and Denali Therapeutics gave 648 people with early Parkinson’s, with or without a LRRK2 mutation, an inhibitor called BIIB122 or a placebo for 48 to 144 weeks (Biogen and Denali). The drug did not slow the disease, even though blood tests showed that it blocked more than 90% of LRRK2 activity, and the firms stopped developing it for Parkinson’s with no known genetic cause. Denali is continuing a smaller trial, BEACON, in people who carry a LRRK2 mutation and have already been diagnosed. It is registered as a study of about 50 participants that measures safety over 12 weeks, along with drug levels and biomarkers (ClinicalTrials.gov). The mouse results point to treating carriers before symptoms appear, but neither LUMA nor BEACON was designed to test that. BEACON’s results, due in the first half of 2027, will report on safety and biomarkers in carriers who already have the disease.