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Related Experiment Video

Updated: Jul 7, 2025

Human Peripheral Blood Neutrophil Isolation for Interrogating the Parkinson's Associated LRRK2 Kinase Pathway by Assessing Rab10 Phosphorylation

Human Peripheral Blood Neutrophil Isolation for Interrogating the Parkinson's Associated LRRK2 Kinase Pathway by Assessing Rab10 Phosphorylation

Published on: March 21, 2020

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.

Journal of Peptide Science : an Official Publication of the European Peptide Society

|December 23, 2023

Summary

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).

Keywords:

LRRK2 LRRK2 inhibitors Parkinson's disease centrosomal cohesion ciliogenesis constrained peptides

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Last Updated: Jul 7, 2025

Human Peripheral Blood Neutrophil Isolation for Interrogating the Parkinson's Associated LRRK2 Kinase Pathway by Assessing Rab10 Phosphorylation

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Published on: March 21, 2020

Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate-binding Tag

Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate-binding Tag

Published on: December 14, 2017

Assaying the Kinase Activity of LRRK2 in vitro

Assaying the Kinase Activity of LRRK2 in vitro

Published on: January 18, 2012

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.