Combined Knockout of Lrrk2 and Rab29 Does Not Result in Behavioral Abnormalities in vivo

Abstract

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.

Increased LRRK2 kinase activity alters neuronal autophagy by disrupting the axonal transport of autophagosomes

“…These observations are consistent with reports that LRRK2 and Rab29 act within the same pathway. 52,53 LRRK2 kinase inhibition rescues AV transport in Rab29overexpressing neurons Next, we tested whether Rab29 overexpression affects AV transport through activation of LRRK2 kinase activity; if so, the LRRK2 kinase inhibitor MLi-2 should rescue defective transport in Rab29-overexpressing cells. While the comigration of axonal LC3 and Rab29 vesicles was not affected by MLi-2 (Figure S6H), LRRK2 kinase inhibition significantly reduced pause number, fraction of time paused, and D run length of axonal AVs in WT neurons expressing EGFP-Rab29 (Figures 5H-5J).…”

Significance of Parkinson Family Genes in the Prognosis and Treatment Outcome Prediction for Lung Adenocarcinoma

“…At the same time, oxidative stress and inflammation caused by an imbalance of lipid metabolism also contribute to the occurrence and development of PD ( Alecu and Bennett, 2019 ). In addition, RAB29 is believed to cause PD via lysosomal dysfunction, while CHCHD2 may cause PD by impairing mitochondrial function ( Zhou et al, 2019 ; Mazza et al, 2021 ). These processes are also of major relevance in tumours, providing an avenue for their further investigation in cancer.…”

Rab GTPases in Parkinson's disease: a primer

“…In addition, studies in Caenorhabditis elegans show that homologues of these two proteins act coordinately to regulate axon morphology [ 60 ]. Whilst knockout of Rab29, LRRK2 or both is not associated with any brain pathology [ 60 , 61 ], double-knockout of Rab29 and LRRK2 causes non-additive lysosomal defects and pathology in the kidney [ 60 ], consistent with these two proteins acting in converging pathways.…”