Two research teams led by NIA researchers have reported discovering mechanisms that suggest the biological role of leucine-rich repeat kinase-2 (LRRK2) gene in the development of Parkinson’s disease. By better understanding how the disease develops, researchers may be able to develop new treatments for Parkinson’s. These new findings were reported in Science Advances and Science Translational Medicine.
Many different gene mutations are implicated in the development of Parkinson’s. In 2004, NIA researchers and others discovered that LRRK2 gene mutations cause Parkinson’s. The mutation results in the gene making a toxic LRRK2 protein. Now, research teams are trying to better understand the roles of the protein in the body and how it causes disease.
LRRK2 activity with lysosomes
Since its discovery, LRRK2 protein has been found to have many biological roles. In one recent study, an NIA research team set out to determine how LRRK2 affects the function of lysosomes, a component of cells that contain enzymes that break down and recycle substances. Previous human genetic studies have implicated lysosomes in Parkinson’s.
The research team studied lysosomes within mouse astrocytes, which are star-shaped cells that help anchor neurons in the brain. The team discovered that LRRK2 orchestrates how enzymes and other substances are released in astrocytes. More research is needed to determine whether the pathway is more active in people with LRRK2 gene mutations and whether it contributes to neuron death in Parkinson’s.
LRRK2 activity with microglia
Whereas the first NIA research team used astrocytes, the second team studied the role of LRRK2 in activating microglia from mice. Microglia are immune cells that act as trash collectors, a function that is essential for the brain to function properly.
In people with Parkinson's, neurons contain Lewy bodies, which are abnormal clumps of alpha-synuclein protein. Previously, the team showed in mice that alpha-synuclein released from neurons can cause microglia to release toxic inflammatory substances, which then causes brain inflammation. In this study, the team discovered that when neurons release alpha-synuclein, LRRK2 proteins in microglia are activated. Their tests showed that LRRK2 plays a role in both brain inflammation and neuron damage in mice.
Next, the team analyzed brain samples from eight healthy adults and 10 people who had Parkinson’s disease or dementia with Lewy bodies. The samples were from the NIA-funded Alzheimer Disease Research Center at the University of California, San Diego. Lab tests revealed that people with Parkinson’s or dementia with Lewy bodies were more likely than the healthy adults to have evidence of the same activated pathway that the team identified in mice. This finding suggests that a drug that inhibits LRRK2 might help people with Parkinson’s or dementia with Lewy bodies.
After that, the team gave an LRRK2 inhibitor drug to mice genetically modified to have a Parkinson-like disease. The drug reduced neuron loss, inflammatory substances in the brain, and behavior and learning deficits. Now the research team is planning other mouse studies to explore combining the LRRK2 inhibitor drug with a drug that blocks alpha-synuclein activity. That combination may reduce the risk of unwanted side effects.
Both projects were supported in part by NIA and the NIH Intramural Research Program.
These activities relate to NIH's AD+ADRD Research Implementation Milestone 2.M, “Identify mechanisms by which Lewy body diseases may spread between and affect different brain regions and how Lewy bodies interact with other pathologies.” They also relate to Milestone 2.B, “Establish new research programs that employ data-driven, systems-based approaches to understand the interaction between peripheral systems (in particular: immune, metabolic, microbiome) and the brain and the impact of this interaction on brain aging and neurodegeneration. These efforts should integrate human and animal model research and characterize the extent to which molecular (epigenomic, transcriptomic and metabolomic) variation identified in peripheral tissues can be used as a proxy for inter-individual variation in the trajectories of brain aging, AD and AD-related dementias.”
References: Bonet-Ponce L, et al. LRRK2 mediates tubulation and vesicle sorting from lysosomes. Science Advances. 2020;6(46):eabb2454. doi: 10.1126/sciadv.abb2454.
Kim C, et al. LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies. Science Translational Medicine. 2020;12(565):eaay0399. doi: 10.1126/scitranslmed.aay0399.