PAK6 rescues pathogenic LRRK2-mediated ciliogenesis and centrosomal cohesion defects in a mutation-specific manner.

P21 activated kinase 6 (PAK6) is a serine-threonine kinase with physiological expression enriched in the brain and overexpressed in a number of human tumors. While the role of PAK6 in cancer cells has been extensively investigated, the physiological function of the kinase in the context of brain cells is poorly understood. Our previous work uncovered a link between PAK6 and the Parkinson's disease (PD)-associated kinase LRRK2, with PAK6 controlling LRRK2 activity and subcellular localization via phosphorylation of 14-3-3 proteins.

A potential patient stratification biomarker for Parkinson´s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells.

Parkinson´s disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types.

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

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.

Targeting LRRK2 mRNA stability in Parkinson's disease.

In a recent study, Liu and colleagues demonstrated a role for the purine biosynthesis enzyme ATIC and its substrate in regulating the protein levels of the Parkinson's disease kinase LRRK2, which rescues neurodegeneration and neuroinflammation in distinct animal models. This work highlights a novel avenue to target LRRK2 protein levels as a strategy to prevent neurodegeneration in Parkinson's disease.

Insights into the cellular consequences of LRRK2-mediated Rab protein phosphorylation.

Point mutations in leucine-rich repeat kinase 2 (LRRK2) which cause Parkinson's disease increase its kinase activity, and a subset of Rab GTPases have been identified as endogenous LRRK2 kinase substrates. Their phosphorylation correlates with a loss-of-function for the membrane trafficking steps they are normally involved in, but it also allows them to bind to a novel set of effector proteins with dominant cellular consequences. In this brief review, we will summarize novel findings related to the LRRK2-mediated phosphorylation of Rab GTPases and its various cellular consequences in vitro and in the intact brain, and we will highlight major outstanding questions in the field.

Protocol to measure centrosome cohesion deficits mediated by pathogenic LRRK2 in cultured cells using confocal microscopy.

The present protocol allows for quantification of inter-centrosome distances in G2 phase cells by confocal fluorescence microscopy to determine centrosome cohesion deficits. We describe transfection and immunofluorescence approaches followed by image acquisition and analysis of inter-centrosome distances. This protocol is for adherent A549 cells transiently overexpressing pathogenic LRRK2 and for immortalized murine embryonic fibroblasts endogenously expressing LRRK2 but is amenable to any other cultured cell type as well.

The LRRK2 signaling network converges on a centriolar phospho-Rab10/RILPL1 complex to cause deficits in centrosome cohesion and cell polarization.

The Parkinson's-disease-associated LRRK2 kinase phosphorylates multiple Rab GTPases including Rab8 and Rab10, which enhances their binding to RILPL1 and RILPL2. The nascent interaction between phospho-Rab10 and RILPL1 blocks ciliogenesis in vitro and in the intact brain, and interferes with the cohesion of duplicated centrosomes in dividing cells. We show here that regulators of the LRRK2 signaling pathway including vps35 and PPM1H converge upon causing centrosomal deficits.

Pathogenic LRRK2 regulates centrosome cohesion via Rab10/RILPL1-mediated CDK5RAP2 displacement.

Mutations in LRRK2 increase its kinase activity and cause Parkinson's disease. LRRK2 phosphorylates a subset of Rab proteins which allows for their binding to RILPL1. The phospho-Rab/RILPL1 interaction causes deficits in ciliogenesis and interferes with the cohesion of duplicated centrosomes.

Rab GTPases in Parkinson's disease: a primer.

Parkinson's disease is a prominent and debilitating movement disorder characterized by the death of vulnerable neurons which share a set of structural and physiological properties. Over the recent years, increasing evidence indicates that Rab GTPases can directly as well as indirectly contribute to the cellular alterations leading to PD. Rab GTPases are master regulators of intracellular membrane trafficking events, and alterations in certain membrane trafficking steps can be particularly disruptive to vulnerable neurons.

LRRK2-Related Parkinson's Disease Due to Altered Endolysosomal Biology With Variable Lewy Body Pathology: A Hypothesis.

Mutations in the gene encoding for leucine-rich repeat kinase 2 (LRRK2) are associated with both familial and sporadic Parkinson's disease (PD). LRRK2 encodes a large protein comprised of a GTPase and a kinase domain. All pathogenic variants converge on enhancing LRRK2 kinase substrate phosphorylation, and distinct LRRK2 kinase inhibitors are currently in various stages of clinical trials.