Parkinson’s disease (PD), a neurodegenerative disease that causes both motor and non-motor symptoms, affects about 10 million people worldwide. Treating the disease is complex for a number of reasons, including the fact that no two people experience the disease in precisely the same way.
Scientists believe that about 25 percent of Parkinson’s disease cases are caused by genetic mutations, with one particular mutation at the center of a Stanford Medicine study recently published in Science Signaling. The study focused on a single genetic mutation that overstimulates the leucine-rich repeat kinase 2 (LRRK2) enzyme, a large, multi-domain scaffolding enzyme with strong links to PD. The study found that inhibiting this enzyme could “rescue” vulnerable neurons in the LRRK2-mutant mouse model of PD. Read on for a summary of the research.
Working Backward to Treat Parkinson’s Disease
As we mentioned above, a significant percentage of PD cases are linked to a genetic mutation that causes the LRRK2 enzyme to be overactive. A surge of LRRK2 activity has far-reaching consequences, changing the structure of brain cells and impacting key neurotransmitters and cells in the striatum. This brain region is essential for both motor skills and non-motor skills, including motivation and decision-making.
Overactive LRRK2 enzymes also disrupt communication between neurons by eliminating cells’ primary cilia. Cilia act like antennae, helping facilitate chemical messages between neurons. The researchers hypothesized that cilia loss should be treated as a precursor to cell death. “Many kinds of processes necessary for cells to survive are regulated through cilia sending and receiving signals,” wrote study senior author Suzanne Pfeffer, the Emma Pfeiffer Merner Professor of Medical Sciences and a professor of biochemistry at Stanford University, in a university press release. With this in mind, the goal of the study was to test a potential intervention meant to reverse the effects of too much LRRK2 enzyme activity: an MLi-2 LRRK2 kinase inhibitor.
Are Kinase Inhibitors the Key?
LRRK2 is a kinase — a type of enzyme that transfers phosphates to other molecules. By working with a kinase inhibitor, the team hypothesized, they could potentially dampen the overactive LRRK2 response linked to some PD cases. They selected MLi-2, described in the study abstract as “a brain-penetrant, selective, and now experimental inhibitor of LRRK2,” as a candidate for oral administration to mice bred to express PD symptoms.
Restoring Neurons in LRRK2-Mutant Mice
The scientists worked with the LRRK2-mutant mouse model of PD, which shows symptoms consistent with early Parkinson’s disease. They started by feeding the mice MLi-2 for two weeks. The results were lackluster: The team detected no changes in brain structure, signaling, or the viability of the dopamine neurons, which are frequently damaged as PD progresses.
After those disappointing results, the team decided to administer the inhibitor for a longer period of time: three months. This time, after the administration period concluded, the mice showed promising results. At the cellular level, the percentage of striatal neurons and glia was indistinguishable when comparing LRRK2 mice treated with MLi-2 with those given a vehicle. But MLi-2-treated LRRK2 mice showed a marked increase in primary cilia, which restored communication between dopaminergic neurons and the striatum. Perhaps most shockingly, markers of the density of dopamine nerve endings within the striatum doubled. This suggests that neurons that had been in the process of dying recovered after MLi-2 treatment. In other words, the neurons seemed to come back from the brink of death after treatment.
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The next step for the research team is to test whether other forms of Parkinson’s disease — forms that are not associated with the LRRK2 mutation — could benefit from this type of treatment. “These findings suggest that it might be possible to improve, not just stabilize, the condition of patients with Parkinson’s disease,” wrote Suzanne Pfeffer in a university press release. Ideally, people with the LRRK2 genetic mutation should be able to start an enzyme-inhibiting treatment as soon as possible.
To evaluate the effect of LRRK2 in vivo, Scantox Neuro offers research with an LRRK2 rat model and additional rodent models developed by and available from the Michael J. Fox Foundation (MJFF) and its partners. Additionally, we offer related (MLi-2) treatment and analysis options, including behavioral tests and biochemical and histological analyses.
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