A Parkinson’s-linked mutation disrupts dopamine release in vulnerable brain cells before detectable neuron loss, research suggests.
The findings could help researchers develop treatments aimed at the earliest stages of Parkinson’s disease.
Loukia Parisiadou is assistant professor of pharmacology and senior author of the study.
The researcher said: “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.”
The Northwestern Medicine team studied LRRK2, one of the most common genetic causes of Parkinson’s disease.
Using advanced genetic, imaging and protein-analysis techniques, researchers found that disease-causing LRRK2 mutations impair groups of dopamine-producing neurons that are particularly vulnerable to degeneration.
Parkinson’s disease is marked by the loss of dopamine-producing neurons in the substantia nigra, a part of the brain involved in movement.
Not all neurons in this region are affected equally. Some are highly vulnerable, while others remain relatively resistant, and the reasons for this have not been fully understood.
The researchers found that LRRK2 was more abundant in the dopamine neuron subtypes most vulnerable to Parkinson’s disease in both mice and humans.
High-resolution imaging showed that mutant LRRK2 disrupted active zones, specialised sites that allow neurons to release dopamine.
As a result, dopamine release was reduced in living mice, particularly in circuits linked to the most vulnerable dopamine neuron populations.
Parisiadou said: “What we found here is that pathogenic mutation of LRRK2 affects the dopamine neuron subtypes that are particularly vulnerable in Parkinson’s disease.
“This directly links a major Parkinson’s disease gene to selective neuron vulnerability.”
The researchers also identified a possible molecular explanation for the disruption.
Mutant LRRK2 increased the phosphorylation of RAB3 proteins. Phosphorylation is a chemical process that can change how a protein behaves.
This interfered with their interactions with RIM1 and RIM2, which are needed to organise the sites where neurons release dopamine.
The changes appeared to affect the structure and function of synapses, the junctions through which brain cells communicate, before any detectable neurons had been lost.
The researchers also measured dopamine release in awake, moving animals, giving them a clearer view of how the disease process develops.
Parisiadou said: “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.
“This is the core of Parkinson’s disease: loss of dopamine release in these neurons when an animal is moving.”
The findings support growing evidence that problems with communication between neurons may be among the earliest changes in Parkinson’s disease, rather than the death of the neurons themselves.
Previous studies by Parisiadou’s laboratory suggested that problems in dopamine-receiving cells can develop before symptoms appear.
The latest findings offer an explanation for how this process may begin within the vulnerable neurons themselves.
Parisiadou said the research could also support the development of more targeted treatments. Several therapies aimed at LRRK2 are already in clinical development.
She said: “This work can create a platform for testing treatments more precisely.
“Now we can evaluate those in the specific neuronal populations that are actually vulnerable to Parkinson’s.”
Rather than relying only on broad measures of drug activity across the brain, researchers could assess whether experimental treatments restore dopamine signalling in the neurons most affected by the disease.
The findings may be particularly important because they identify a possible treatment window before irreversible damage occurs.
Parisiadou said: “What we found is that these mutations affect the function of these neurons even before the overt loss.
“If we understand what mechanisms are behind the dysfunction of these vulnerable neurons early, then we can perhaps do better, and target early these neurons and achieve disease-modifying therapies.”
