Stanford Medicine researchers have uncovered a promising way to reverse early signs of Parkinson’s disease—by inhibiting a specific overactive enzyme. In a new mouse study, scientists discovered that reducing activity of an enzyme called leucine-rich repeat kinase 2 (LRRK2) could restore communication between brain cells and potentially rescue neurons from degeneration.
The Problem with Overactive LRRK2
A common genetic mutation causes LRRK2 to become hyperactive. This disrupts how dopamine-producing neurons communicate with cells in the striatum—a brain region involved in movement, motivation, and decision-making. Excess LRRK2 activity alters the structure of neurons and causes them to lose their primary cilia, small antenna-like structures that send and receive vital chemical messages.
Without these cilia, cells become functionally disconnected—similar to a mobile phone losing its network. This breakdown in signaling prevents neurons and glial cells in the striatum from responding to distress signals and producing neuroprotective proteins that keep brain cells alive.
The Role of the Sonic Hedgehog Signal
One crucial disrupted pathway involves a molecule called sonic hedgehog, released by dopamine neurons under stress. In a healthy brain, this signal prompts neurons and astrocytes in the striatum to produce protective proteins. However, when LRRK2 is overactive and cilia are lost, the cells can no longer receive the sonic hedgehog signal—putting them on a path toward cell death.
“Cilia are essential for receiving survival signals,” explained senior author Suzanne Pfeffer. “When cells lose cilia, they lose the ability to stay alive.”
Inhibitor Offers a Possible Solution
To counteract this, researchers tested a compound called MLi-2, an LRRK2 kinase inhibitor. This molecule binds to the enzyme and reduces its activity. As per Medical Express, initial trials involved feeding the inhibitor to mice for two weeks, but no noticeable changes occurred in that timeframe.
Inspired by studies on circadian rhythm neurons—which showed that non-dividing cells could regrow cilia—researchers extended the treatment to three months. The results were, in Pfeffer’s words, “astounding.”
Regrowing Cellular Antennae and Restoring Communication
After three months of treatment, the percentage of neurons and glia with primary cilia in mutant mice became nearly identical to that in normal mice. This restoration reestablished signaling between dopamine neurons and striatal cells. As a result, striatal cells resumed producing neuroprotective proteins, while dopamine neurons showed less stress and improved nerve terminal density.
Importantly, this recovery suggests the potential not just to halt but to reverse neuronal damage in early-stage Parkinson’s disease.
Implications for Broader Parkinson’s Treatment
About 25% of Parkinson’s cases stem from genetic mutations, and the LRRK2 mutation is among the most common. However, Pfeffer noted that overactive LRRK2 can occur without a genetic cause. This means that LRRK2 inhibitors like MLi-2 could benefit a broader range of patients—potentially including those with other forms of Parkinson’s or neurodegenerative diseases.
“These findings suggest it might be possible to improve—not just stabilize—patients’ conditions,” Pfeffer said.
Toward Earlier Intervention
The earliest symptoms of Parkinson’s often appear 15 years before motor issues like tremors. These early signs include loss of smell, constipation, and sleep disorders. According to Pfeffer, identifying people with the LRRK2 mutation early could allow preventive treatment with enzyme inhibitors.
The research team now plans to explore whether this approach can help patients without the LRRK2 mutation.
Moving Closer to Clinical Application
“This approach has great promise,” Pfeffer said. “Multiple LRRK2 inhibitor clinical trials are already underway, and we hope our findings in mice will translate to human patients.”
Funding and Collaboration
The study will be published in Science Signaling on July 1. It was a collaborative effort between Stanford University and the University of Dundee, led by Pfeffer and postdoctoral scholar Ebsy Jaimon, PhD. Funding came from The Michael J. Fox Foundation, the Aligning Science Across Parkinson’s initiative, and the UK Medical Research Council.