Researchers at the University of Alabama at Birmingham report that the most common genetic cause of Parkinson’s disease, a mutant form of the LRRK2 enzyme, contributes to the build-up of α-synuclein in neurons — a telltale sign that the nerve cells are destined to die.
Published last week in the Journal of Neuroscience, the stude “G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons,” provides good news that the interaction between mutant LLRK2 and α-synuclein can be prevented with drugs that block the enzyme, potentially preventing the fatal aggregation of the protein.
“These data give us hope for the clinical potential of LRRK2 kinase inhibitors as effective therapies for Parkinson’s disease,” said Laura A. Volpicelli-Daley, PhD, in a news release. “The LRRK2 kinase inhibitors may inhibit the spread of pathologic α-synuclein, not only in patients with LRRK2 mutations, but in all Parkinson’s disease patients.”
The findings might also lead to new treatments for patients with other diseases, such as Lewy body dementia, linked to the aggregation of α-synuclein in the brain.
Researchers studied cultured neurons in lab dishes, and those in living rats to understand how LRRK2 interacts with α-synuclein. To trigger the protein aggregation, they used ‘seeds’ of pre-formed α-synuclein fibrils, which they delivered to neurons. They soon found that the mutant LRRK2 kinase enzyme, known as G2019S-LRRK2, speeded up the formation of aggregates in nerve cells from the hippocampus — a brain region important for memory formation and emotional processing.
Also important for Parkinson’s disease, researchers found that the mutant enzyme speeded up protein aggregation in dopamine neurons from another brain region called the substantia nigra. This area, named for the black colored dopamine neurons constituting it, is the main region affected by neurodegeneration in Parkinson’s. Adding small doses of drugs blocking the actions of the enzyme again slowed the rate of protein aggregation.
In another set of experiments, they could also show that cells holding the mutant LRRK2 enzyme had a larger proportion of ‘mobile’ α-synuclein, not bound to the membrane of the cell. This type of α-synuclein is particularly prone to aggregate, leading the team to speculate that the defective enzyme somehow increases the amount of mobile protein, and so the risk of Parkinson’s.
“Future studies to validate the safety and efficacy of the LRRK2 inhibitors will be necessary before testing the inhibitors in human clinical trials,” Volpicelli-Daley said.
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