Parkinson's Breakthrough Could Help Prevent Brain Cell Loss

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A new treatment for one type of Parkinson's disease may be on the horizon after researchers discovered a "brake" that can halt cell death.
The study, led by researchers from Stanford University, California, involved a form of the neurodegenerative disorder that is caused by a single genetic mutation.
This mutation causes an excess of a protein that interferes with the brain's ability to protect itself. Inhibiting this protein, the team found, can halt the damage and even allow dying neurons to recover.
"These findings suggest that it might be possible to improve, not just stabilize, the condition of patients with Parkinson's disease," said paper author and Stanford biochemist professor Suzanne Pfeffer in a statement. Key, however, will be "if patients can be identified early enough," she added.
While Parkinson's most recognizable symptom might be resting tremors, the earliest signs of the disease typically manifest some 15 years earlier.
These first signs, Pfeffer said, include constipation, a loss of smell and REM sleep behavior disorder, a condition in which people act out their dreams while sleeping.
Artist's impression of neurons in the brain.
Artist's impression of neurons in the brain.
FlashMovie/iStock / Getty Images Plus
In the U.S, it is estimated that some 1.1 million people are living with Parkinson's disease—a figure only expected to rise in the near future, according to the Parkinson's Foundation.
As Pfeffer and colleagues explain, around a quarter of all cases are caused by genetic mutations, with one of the most common being one that increases the activity of an enzyme called leucine-rich repeat kinase 2 (LRRK2).
Too much LRRK2 in the brain changes the structure of cells by causing them to lose their "antenna" (technically the primary cilia) that allows them to send and receive chemical messages.
In a healthy brain, communications are relayed back and forth between dopamine neurons in two regions of the brain known as the striatum and the substantia nigra.
When dopamine neurons are stressed, they release a protein-based signal in the striatum called sonic hedgehog (after the video game character)—this causes neurons and support cells to produce so-called neuroprotective factors that shield other cells from dying.
When LRRK2 activity crosses a certain threshold, the loss of the primary cilia in the cells of the striatum prevents them from receiving the sonic hedgehog signal; as a result, the neuroprotective factors are not produced.
"Many kinds of processes necessary for cells to survive are regulated through cilia sending and receiving signals," explained Pfeffer.
"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."
A diagram shows how neurons (blue) rooted in the substantia nigra provide dopamine (dark green dots) to striatal neurons (red).
A diagram shows how neurons (blue) rooted in the substantia nigra provide dopamine (dark green dots) to striatal neurons (red).
Emily Moskal / Stanford Medicine
It is possible to combat an excess of LRRK2 using a so-called "MLi-2 LRRK2 kinase inhibitor," a molecule that attaches to the enzyme and reduces its activity.
In their study, Pfeffer and colleagues set out to test whether this inhibitor could also reverse the effects of too much LRRK2, as well as whether it was even possible for fully mature neurons and supportive glia to regrow lost cilia and regain their communication ability.
At first, the results were not promising. The team gave the inhibitor for two weeks to mice that had the LRRK2 mutation (and show symptoms consistent with early Parkinson's disease)—to no effect.
However, the researchers were inspired by recent studies into sleep-wake cycles, which found that the primary cilia on the mature cells involved 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," said Pfeffer.
Inspired by this, the team decided to try giving the mice the inhibitor for a longer time—with the results at three months being "astounding," the biochemist added.
The longer treatment saw the percentage of striatal neurons and glia with primary cilia in the mice with the mutation increase to the same level as regular, healthy mice.
This had the effect of restoring communication between the dopamine neurons and the striatum, leading to the normal secretion of neuroprotective factors.
The researchers also found that the level of hedgehog signaling from the dopamine neurons decreased—suggesting that they were under less stress.
Moreover, the density of dopamine nerve endings in the mice's striatum was found to double, suggesting that neurons which had been in the process of dying had recovered.
LRRK2 inhibition decreased stress in dopamine neurons in mice models of Parkinson's (top right vs. bottom right—with healthy mice on the left for comparison.)
LRRK2 inhibition decreased stress in dopamine neurons in mice models of Parkinson's (top right vs. bottom right—with healthy mice on the left for comparison.)
Ebsy Jaimon & Suzanne Pfeffer
With their initial study complete, the researchers say that their next step would be to determine whether other forms of Parkinson's that are not associated with the LRRK2 mutation could also benefit from the new treatment.
This is possible, Pfeffer explains, because the mutation is not the only way to end up with an overactive LRRK2 enzyme. In fact, she added, the inhibitor treatment might even help with other neurodegenerative diseases.
"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, said Pfeffer.
She concluded: "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."
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Reference
Jaimon, E., Lin, Y.-E., Tonelli, F., Antico, O., Alessi, D. R., & Pfeffer, S. R. (2025). Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinson's disease–linked LRRK2-mutant mice. Science Signaling, 18(793). https://doi.org/10.1126/scisignal.ads5761