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Inhibiting enzyme could halt cell death in Parkinson’s disease, study finds

Slowing cell death in Parkinson’s disease

2025-07-01
(Press-News.org) Putting the brakes on an enzyme might rescue neurons that are dying due to a type of Parkinson’s disease that’s caused by a single genetic mutation, according to a new Stanford Medicine-led study conducted in mice.

The genetic mutation causes an enzyme called leucine-rich repeat kinase 2, or LRRK2, to be overactive. Too much LRRK2 enzyme activity changes the structure of brain cells in a way that disrupts crucial communication between neurons that make the neurotransmitter dopamine and cells in the striatum, a region deep in the brain that is part of the dopamine system and is 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.

Pfeffer added that because the genetic mutation is not the only way to end up with overactive LRRK2 enzyme, the inhibitor treatment might help with other types of Parkinson’s disease or even other neurodegenerative diseases.

Pfeffer is the senior author of the study to be published in Science Signaling on July 1. Ebsy Jaimon, PhD, a postdoctoral scholar in biochemistry, is the lead author. The work is part of a longstanding collaboration with Dario Alessi, PhD, at the University of Dundee in Scotland.

Cellular antennae

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.

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.

Restored cilia were unexpected

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.

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 restored communication between dopamine neurons and the striatum.

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.

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.”

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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About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu.

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[Press-News.org] Inhibiting enzyme could halt cell death in Parkinson’s disease, study finds
Slowing cell death in Parkinson’s disease