The study, “LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic neurons from patients with Parkinson’s disease,” appeared in the journal Proceedings of the National Academy of Sciences.
Parkinson’s is characterized by a substantial loss of neurons that produce the neurotransmitter dopamine in a brain area called substantia nigra. Prior research conducted by a team led by Dimitri Krainc, MD, PhD, chair and Aaron Montgomery Ward Professor of Neurology at Northwestern, showed that the accumulation of oxidized dopamine in the brain regulates the death of these neurons, which leads to Parkinson’s motor symptoms.
In neurons, neurotransmitters are stored in tiny vesicles near the synapse. Scientists have recently found genes associated with Parkinson’s involved in the transport of vesicles from these synaptic terminals toward the cell’s interior, a process called endocytosis. Through endocytosis, neurons replenish the levels of neurotransmitters to enable continued communication.
This discovery supported the importance of impaired neuronal communication, or synaptic dysfunction, in disease development, but the precise mechanisms leading to neuronal death remained unknown.
“In this paper, we further explain how such oxidized dopamine is formed in synaptic terminals of neurons from patients with Parkinson’s,” Krainc, the study’s senior author, said in a press release.
Results showed that a mutated form of the Parkinson’s-associated enzyme LRRK2 dysregulates auxilin, a protein normally responsible for synaptic vesicle endocytosis. This led to faulty endocytosis and decreased density of vesicles in patient-derived dopaminergic neurons.
Importantly, the scientists also observed that impaired endocytosis led to accumulation of oxidized dopamine in neurons. In turn, this buildup of toxic dopamine caused Parkinson’s-related effects, including an increase in alpha-synuclein, the main component of protein clumps called Lewy bodies.
“Together, this work suggests that mutant LRRK2 disrupts synaptic vesicle endocytosis, leading to altered dopamine metabolism and dopamine-mediated toxic effects in patient-derived dopaminergic neurons,” the investigators wrote in the study.
“These findings suggest that early therapeutic intervention in dysfunctional presynaptic terminals may prevent downstream toxic effects of oxidized dopamine and neurodegeneration in [Parkinson’s],” Krainc said in the release.
Additionally, investigating genetic forms of Parkinson’s contributes to increased understanding of key cellular mechanisms in the development of the disease, the researchers noted.
“This study is another example of how the emergence of genetic causes of Parkinson’s has helped us understand how disease develops and where to focus to identify key pathways and targets for drug development,” Krainc said.