Combined Knockout of Lrrk2 and Rab29 Does Not Result in Behavioral Abnormalities in vivo
Melissa Conti Mazza1, Victoria Nguyen1,2, Alexandra Beilina1
1Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Background:
Coding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson's disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, suggesting that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD.
Objective:
Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, we set out to determine whether there are any consequences on brain function with aging after deletion of both genes.
Methods:
We generated a double knockout mouse model and performed a battery of motor and non-motor behavioral tests. We then investigated postmortem assays to determine the presence of PD-like pathology, including nigral dopamine cell count, astrogliosis, microgliosis, and striatal monoamine content.
Results:
Behaviorally, we noted only that 18-24-month Rab29-/- and double (Lrrk2-/-/Rab29-/-) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in the outcomes that represented PD-like pathology.
Conclusion:
These results suggest that depletion of both LRRK2 and RAB29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans.
Insights
Deleting both LRRK2 and RAB29 genes in mice did not result in Parkinson's disease pathology. This suggests that targeting this pathway may be a safe therapeutic strategy for Parkinson's disease in humans.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene are a cause of familial Parkinson's disease (PD).
- Increased LRRK2 kinase activity is a direct result of these mutations, indicating potential therapeutic benefit from enzyme inhibition.
- Genetic studies link LRRK2 and its substrate RAB29 to sporadic PD risk.
Purpose of the Study:
- To investigate the effects of deleting both LRRK2 and RAB29 genes on brain function during aging.
- To assess potential consequences of combined gene deletion on PD-like pathology.
Main Methods:
- Generation of a double knockout mouse model (Lrrk2-/-/Rab29-/-).
- Comprehensive behavioral testing for motor and non-motor functions.
- Postmortem analysis of PD-related pathology, including dopaminergic neuron counts and neuroinflammation markers.
Main Results:
- Mice lacking both LRRK2 and RAB29 showed reduced locomotor activity in aged individuals (18-24 months).
- No significant differences in PD-like pathological markers were observed between knockout and wildtype mice.
Conclusions:
- The combined depletion of LRRK2 and RAB29 is well-tolerated in mice.
- These findings support the potential for safely targeting the LRRK2-RAB29 pathway for Parkinson's disease therapeutics in humans.
