Targeting Rab‐RILPL interactions as a strategy to downregulate pathogenic LRRK2 in Parkinson's disease

Author:

Alexander Krista K.1,Naaldijk Yahaira2,Fasiczka Rachel2,Brahmia Besma2,Chen Tiancheng1,Hilfiker Sabine2,Kennedy Eileen J.1ORCID

Affiliation:

1. Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy University of Georgia Athens GA USA

2. Department of Anesthesiology Rutgers New Jersey Medical School Newark NJ 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.

Funder

Michael J. Fox Foundation for Parkinson's Research

Publisher

Wiley

Subject

Organic Chemistry,Drug Discovery,Pharmacology,Molecular Biology,Molecular Medicine,General Medicine,Biochemistry,Structural Biology

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