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

Abstract

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. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they acumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate PD patients who will benefit from LRRK2-related therapeutics.

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

“…The interaction between phosphorylated Rab8a and Rab10 and RILPL proteins at the mother centriole/ciliary base was found to cause both ciliary and centrosomal cohesion defects in various cell types in vitro [13,17,[19][20][21][22]. Physiologically, these pRab-RILPL complexes also cause deficits in centrosome cohesion including in primary or immortalized lymphocytes from LRRK2-PD patients as compared to healthy controls [20,23,24]. Further, these effects can be reversed using ATP-competitive LRRK2 inhibitors, demonstrating the instrumental role of hyperactive LRRK2 in initiating ciliogenesis and cohesion defects.…”