Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout
Laura Pellegrini1,2, David N Hauser1, Yan Li3
1Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD, USA.
Abstract:
Mutations in leucine-rich repeat kinase 2 (LRRK2) segregate with familial Parkinson's disease (PD) and genetic variation around LRRK2 contributes to risk of sporadic disease. Although knockout (KO) of Lrrk2 or knock-in of pathogenic mutations into the mouse germline does not result in a PD phenotype, several defects have been reported in the kidneys of Lrrk2 KO mice. To understand LRRK2 function in vivo, we used an unbiased approach to determine which protein pathways are affected in LRRK2 KO kidneys. We nominated changes in cytoskeletal-associated proteins, lysosomal proteases, proteins involved in vesicular trafficking and in control of protein translation. Changes were not seen in mice expressing the pathogenic G2019S LRRK2 mutation. Using cultured epithelial kidney cells, we replicated the accumulation of lysosomal proteases and demonstrated changes in subcellular distribution of the cation-independent mannose-6-phosphate receptor. These results show that loss of LRRK2 leads to co-ordinated responses in protein translation and trafficking and argue against a dominant negative role for the G2019S mutation.
Insights
Loss of leucine-rich repeat kinase 2 (LRRK2) in mice causes kidney defects by altering protein translation and trafficking pathways. The common G2019S mutation did not show these effects, suggesting a different mechanism in Parkinson's disease.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Mutations in leucine-rich repeat kinase 2 (LRRK2) are linked to familial and sporadic Parkinson's disease (PD).
- Lrrk2 knockout (KO) mouse models exhibit kidney defects, but the underlying molecular pathways are not fully understood.
- The role of LRRK2 in kidney physiology and disease pathogenesis requires further investigation.
Purpose of the Study:
- To identify protein pathways affected by LRRK2 loss in mouse kidneys using an unbiased approach.
- To investigate the functional consequences of LRRK2 deficiency in kidney epithelial cells.
- To determine if the pathogenic LRRK2 G2019S mutation causes similar cellular defects.
Main Methods:
- Unbiased proteomic analysis of Lrrk2 KO mouse kidneys.
- Cultured mouse kidney epithelial cells.
- Analysis of lysosomal proteases and mannose-6-phosphate receptor localization.
Main Results:
- Loss of LRRK2 in kidneys is associated with changes in cytoskeletal proteins, lysosomal proteases, vesicular trafficking proteins, and protein translation regulators.
- Cultured kidney cells lacking LRRK2 showed accumulation of lysosomal proteases and altered subcellular distribution of the cation-independent mannose-6-phosphate receptor.
- Mice expressing the LRRK2 G2019S mutation did not exhibit these kidney-related protein pathway changes.
Conclusions:
- Loss of LRRK2 function in vivo leads to coordinated alterations in protein translation and lysosomal trafficking pathways within the kidney.
- These findings suggest that LRRK2 deficiency, rather than a dominant-negative effect of the G2019S mutation, underlies the observed kidney defects.
- Understanding LRRK2's role in kidney function may provide insights into PD pathogenesis and potential therapeutic targets.
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