In a breakthrough study, scientists found that silencing a single overactive enzyme in the brain reversed early damage caused by a Parkinson’s-related mutation in mice.
The treatment restored the brain cells’ ability to communicate, regrew tiny cellular “antennae,” and reignited a protective signaling system crucial for neuron survival. After just three months of enzyme inhibition, brain cells once on the brink of death were functioning more like those in healthy mice—offering an exciting glimpse into a future where Parkinson’s symptoms could not just be slowed, but partially reversed.
Turning Off a Damaging Enzyme Could Rescue Brain Cells
Slowing down a single overactive enzyme may help protect brain cells from dying in a form of Parkinson’s disease caused by a specific genetic mutation, according to a new study led by Stanford Medicine.
The mutation ramps up activity of an enzyme called LRRK2 (short for leucine-rich repeat kinase 2). When LRRK2 becomes too active, it disrupts how brain cells are structured and how they communicate. This breakdown affects dopamine-producing neurons and their ability to connect with the striatum, a brain region deeply involved in movement, motivation, and decision-making.
“Findings from this study suggest that inhibiting the LRRK2 enzyme could stabilize the progression of symptoms if patients can be identified early enough,” said Suzanne Pfeffer, PhD, the Emma Pfeiffer Merner Professor in Medical Sciences and a professor of biochemistry. Researchers can mitigate overactive LRRK2 using MLi-2 LRRK2 kinase inhibitor, a molecule that attaches to the enzyme and decreases its activity.
International Team Targets Rogue Kinase
Importantly, Pfeffer noted that this enzyme doesn’t just become overactive because of one genetic mutation. Since other forms of Parkinson’s may also involve elevated LRRK2 activity, this approach could have broader potential, possibly even for other neurodegenerative conditions.
The study, published on July 1 in Science Signaling, was a collaboration with researchers from the University of Dundee in Scotland. Ebsy Jaimon, PhD, a postdoctoral scholar in biochemistry, led the research under Pfeffer’s supervision.
Cellular Antennae and Lost Communication
About 25% of Parkinson’s disease cases are caused by genetic mutations, and the single genetic mutation that makes the LRRK2 enzyme too active is one of the most common. An overactive LRRK2 enzyme causes cells to lose their primary cilia, a cellular appendage that acts like an antenna, sending and receiving chemical messages. A cell that has lost its primary cilia is like your mobile phone when the network is down — no messages come through or are sent.
In a healthy brain, many messages are sent back and forth between dopamine neurons in a region of the brain called the substantia nigra and the striatum. These cellular “conversations” are possible because dopamine neuron axons, which are tubular extensions coming off the cell body, reach all the way to the striatum to communicate with neurons and glia, cells that support neuronal function.
Sonic Hedgehog Disruption and Cilia Loss
An important communication that is disrupted by too much LRRK2 enzyme activity occurs when dopamine neurons are stressed and release a signal in the striatum called sonic hedgehog (named after the cartoon character). In a healthy brain, it causes certain neurons and astrocytes, a type of glial support cell, in the striatum to produce proteins called neuroprotective factors. As their name suggests, these proteins help shield other cells from dying. When there is too much LRRK2 enzyme activity, many of the striatal cells lose their primary cilia — and their ability to receive the signal from dopamine neurons. This disruption in sonic hedgehog signaling means that needed neuroprotective factors are not produced.
“Many kinds of processes necessary for cells to survive are regulated through cilia sending and receiving signals. The cells in the striatum that secrete neuroprotective factors in response to hedgehog signals also need hedgehog to survive. We think that when cells have lost their cilia, they are also on the pathway to death because they need cilia to receive signals that keep them alive,” Pfeffer explained.
Testing the Drug’s Ability to Regrow Cilia
The goal of the study was to test if the MLi-2 LRRK2 kinase inhibitor reversed the effects of too much LRRK2 enzyme activity. Because the neurons and glia that were examined in this study were fully mature and no longer reproducing through cell division, the researchers were initially unsure whether cilia could regrow. Working with mice with the genetic mutation that causes overactive LRRK2 and symptoms consistent with early Parkinson’s disease, the scientists first tried feeding the mice the inhibitor for two weeks. There were no changes detected in brain structure, signaling or the viability of the dopamine neurons.
Recent findings on neurons involved in regulating circadian rhythms, or sleep-wake cycles, inspired the researchers to try again. The primary cilia on those cells — which were also no longer dividing — grew and shrank every 12 hours.
“The findings that other non-dividing cells grow cilia made us realize that it was theoretically possible for the inhibitor to work,” Pfeffer said.
Astounding Results After Long-Term Inhibitor Use
The team decided to see what happened after mice with overactive LRRK2 enzyme consumed the inhibitor for a longer period of time; Pfeffer described the results as “astounding.”
After three months of eating the inhibitor, the percentage of striatal neurons and glia typically affected by the overactive LRRK2 enzyme that had primary cilia in mice with the genetic mutation was indistinguishable from that in mice without the genetic mutation. In the same way, moving from an area with spotty cell service to one with good service restores our ability to send and receive text messages; the increase in primary cilia restores communication between dopamine neurons and the striatum.
Neuroprotective Activity and Dopamine Recovery
The striatal neurons and glia were again secreting neuroprotective factors in response to hedgehog signaling from dopamine neurons in the same amounts as the brains of mice without the genetic mutation. The hedgehog signaling from dopamine neurons decreased, suggesting they were under less stress. And, indicators of the density of dopamine nerve endings within the striatum doubled, suggesting an initial recovery for neurons that had been in the process of dying.
“These findings suggest that it might be possible to improve, not just stabilize, the condition of patients with Parkinson’s disease,” Pfeffer said.
Early Detection May Be Key to Success
The earliest symptoms of Parkinson’s disease begin about 15 years before someone notices a tremor. Typically, these symptoms are a loss of smell, constipation and a sleep disorder in which people act out their dreams while still sleeping, according to Pfeffer. She said the hope is that people who have the LRRK2 genetic mutation can start a treatment that inhibits the enzyme as early as possible.
The next step for the research team is to test whether other forms of Parkinson’s disease that are not associated with the LRRK2 genetic mutation could benefit from this type of treatment.
“We are so excited about these findings. They suggest this approach has great promise to help patients in terms of restoring neuronal activity in this brain circuit,” Pfeffer said. “There are multiple LRRK2 inhibitor clinical trials underway, and our hope is that these findings in mice will hold true for patients in the future.”
Reference: 1 July 2025, Science Signaling.
DOI: 10.1126/scsignal.ads5761
The study was funded by The Michael J. Fox Foundation for Parkinson’s Research, the Aligning Science Across Parkinson’s initiative and the United Kingdom Medical Research Council.
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5 Comments
So it must be great to be a mouse, and go to the mouse clinic. For we humans, hopefully this will mean a pathway from clinical trials to efficacy. Hopefully this pathway can be reduced from the normal 40 year span to availability in only 20 years from now. Perhaps if it passes phase 3 trials, we can get this hyper accelerated down to 12 years from now, from the lab to the clinic. It’s important to devise all the exploitation mechanisms so that shareholders can make a lot of money. That’s the really important thing.
My wife will take it now. Why wait
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My husband would try it now before it gets any worse
Would this possibly work for schizophrenia?
When can human trials begin? Will they be only on Parkinson populations with the genetic mutation or include other Parkinson subjects?