Parkinson's disease gene linked to early neuronal dysfunction

Northwestern Medicine scientists have uncovered how a major Parkinson's disease gene disrupts the brain's most vulnerable dopamine-producing neurons before detectable neuronal loss. The study offers new clues for developing treatments that target the disease in its earliest stages, said the study's senior author, Loukia Parisiadou, Ph.D., assistant professor of pharmacology. The findings are published in Nature Communications.

"Our study shows that the disease-linked mutation selectively disrupts the function of neurons that are most vulnerable before those neurons are lost, so that gives us the opportunity to study an earlier and potentially more treatable stage of the disease," Parisiadou said.

Vulnerability traced to LRRK2

In the study, scientists focused on LRRK2, one of the most common genetic causes of Parkinson's disease. Using advanced genetic, imaging and proteomic techniques, investigators discovered that disease-causing mutations in LRRK2 specifically impair the function of populations of dopamine neurons that are known to be especially susceptible to degeneration in Parkinson's disease.

Parkinson's disease is characterized by the loss of dopamine-producing neurons in a region of the brain called the substantia nigra, but not all neurons in the area are equally affected. Some are highly vulnerable, while others remain relatively resilient. The reasons for this selective vulnerability have remained a longstanding mystery, Parisiadou said.

The research team found that LRRK2 is enriched in the dopamine neuron subtypes most vulnerable to Parkinson's disease in both mice and humans. Using high-resolution imaging, the investigators showed that mutant LRRK2 disrupts structures known as active zones: specialized sites that allow neurons to release dopamine. As a result, dopamine release was reduced in living mice, particularly in the neural circuits associated with the most vulnerable dopamine neuron populations.

"What we found here is that a pathogenic mutation of LRRK2 affects the dopamine neuron subtypes that are particularly vulnerable in Parkinson's disease," Parisiadou said. "This directly links a major Parkinson's disease gene to selective neuron vulnerability."

Synapses falter before neurons die

The scientists also identified a potential molecular mechanism underlying the dysfunction. They found that mutant LRRK2 increases phosphorylation of RAB3 proteins, interfering with their interactions with RIM1 and RIM2 that are required to organize dopamine release sites. Those changes appeared to alter the structure and function of synapses before any detectable loss of neurons, according to the study.

The study also measured dopamine release in awake, moving animals, providing a clearer picture of how the disease process unfolds.

"We have the ability to measure dopamine release from these neurons in living animals during movement, so this really makes the finding more physiologically relevant rather than measurements made in isolated cells or bulk brain tissue," Parisiadou said. "This is the core of Parkinson's disease: loss of dopamine release in these neurons when an animal is moving."

The findings support the growing idea that synaptic dysfunction, rather than neuron death itself, may be one of the earliest events in Parkinson's disease. Previous studies from the Parisiadou laboratory have suggested that deficits in dopamine-receiving cells can emerge before symptoms appear, and the new work provides an explanation for how that process may begin in vulnerable neuronal populations themselves.

A clearer path for early testing

Parisiadou said the work could also help accelerate efforts to develop targeted therapies. Several LRRK2-targeting treatments are already in clinical development.

"This work can create a platform for testing treatments more precisely," Parisiadou said. "Now we can evaluate those in the specific neuronal populations that are actually vulnerable to Parkinson's."

Instead of relying solely on broad measures of drug activity throughout the brain, investigators can now examine whether experimental therapies restore in vivo dopamine signaling in the precise neurons most affected by the disease, she said.

The study's findings may be especially important because they identify a window of opportunity before irreversible damage occurs.

"What we found is that these mutations affect the function of these neurons even before the overt loss," Parisiadou said. "If we understand what mechanisms are behind the dysfunction of these vulnerable neurons early, then we can perhaps do better, target these neurons early and achieve disease-modifying therapies."

This article was originally published on MedicalXpress Breaking News-and-Events.