Targeting Rab-RILPL interactions as a strategy to downregulate pathogenic LRRK2 in Parkinson's disease
Krista K Alexander1, Yahaira Naaldijk2, Rachel Fasiczka2
1Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, USA.
Abstract:
Familial Parkinson's disease (PD) is frequently linked to multiple disease-causing mutations within Leucine-Rich Repeat Protein Kinase 2 (LRRK2), leading to aberrant kinase activity. Multiple pathogenic effects of enhanced LRRK2 activity have been identified, including loss of cilia and centrosomal cohesion defects. When phosphorylated by LRRK2, Rab8a and Rab10 bind to phospho-specific RILPL effector proteins. RILPL-mediated accumulation of pRabs proximal to the mother centriole is critical for initiating deficits in ciliogenesis and centrosome cohesion mediated by LRRK2. We hypothesized that Rab-derived phospho-mimics may serve to block phosphorylated Rab proteins from docking with RILPL in the context of hyperactive LRRK2 mutants. This would serve as an alternative strategy to downregulate pathogenic signaling mediated by LRRK2, rather than targeting LRRK2 kinase activity itself. To test this theory, we designed a series of constrained peptides mimicking phosphorylated Switch II derived from Rab8. These RILPL interacting peptides, termed RIP, were further shown to permeate cells. Further, several peptides were found to bind RILPL2 and restore ciliogenesis and centrosomal cohesion defects in cells expressing PD-associated mutant LRRK2. This research demonstrates the utility of constrained peptides as downstream inhibitors to target pathogenic LRRK2 activity and may provide an alternative approach to target specific pathways activated by LRRK2.
Insights
New peptides targeting Rab proteins offer a novel strategy for familial Parkinson's disease (PD). These RILPL interacting peptides (RIPs) may restore cellular functions impaired by mutant Leucine-Rich Repeat Protein Kinase 2 (LRRK2).
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Familial Parkinson's disease (PD) is often associated with mutations in Leucine-Rich Repeat Protein Kinase 2 (LRRK2), causing kinase hyperactivity.
- Hyperactive LRRK2 leads to pathogenic effects, including ciliogenesis defects and centrosomal cohesion loss, mediated by phosphorylated Rab proteins (pRabs) binding to RILPL effectors.
Purpose of the Study:
- To investigate if Rab-derived phospho-mimics can inhibit the pathogenic signaling of LRRK2 by blocking pRab-RILPL interactions.
- To develop an alternative therapeutic strategy for PD by targeting downstream effectors of LRRK2, rather than LRRK2 kinase activity itself.
Main Methods:
- Designed and synthesized constrained peptides (RIPs) mimicking phosphorylated Rab8 Switch II.
- Assessed peptide cell permeability and their ability to bind RILPL2.
- Evaluated RIPs' efficacy in restoring ciliogenesis and centrosomal cohesion in cells expressing mutant LRRK2.
Main Results:
- Several RIPs demonstrated cell permeability and binding to RILPL2.
- Specific RIPs successfully restored ciliogenesis and centrosomal cohesion defects in cellular models of PD-associated mutant LRRK2.
- This indicates that RIPs can effectively downregulate pathogenic LRRK2 signaling.
Conclusions:
- Constrained peptides (RIPs) are effective downstream inhibitors of pathogenic LRRK2 activity.
- RIPs represent a promising alternative therapeutic approach for familial Parkinson's disease by targeting specific LRRK2-activated pathways.
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