JOURNAL OF PARKINSON’S DISEASE | JANUARY 28, 2020

Padmanabhan S, Lanz TA, Gorman D, Wolfe M, Joyce A, Cabrera C, Lawrence-Henderson R, Levers N, Joshi N, Ma T, Liong C, Narayan S, Alcalay RN, Hutten SJ, Baptista MAS and Merchant K.

Journal of Parkinson’s Disease. 2020.

DOI: 10.3233/JPD-191786

This study was peformed using a Simoa® Homebrew assay.

Abstract

The phosphorylated form of LRRK2, pS935 LRRK2, has been proposed as a target modulation biomarker for LRRK2 inhibitors. The primary aim of the study was to characterize and qualify this biomarker for therapeutic trials of LRRK2 inhibitors in Parkinson’s disease (PD). To this end, analytically validated assays were used to monitor levels of pS935 LRRK2 and total LRRK2 in peripheral blood mononuclear cells (PBMCs) from the following donor groups: healthy control, idiopathic PD, and G2019S carriers with and without PD. Neither analyte correlated with age, gender, or disease severity. While total LRRK2 levels were similar across the four groups, there was a significant reduction in pS935 LRRK2 levels in disease-manifesting G2019S carriers compared to idiopathic PD. In aggregate, these data indicate that phosphorylation of LRRK2 at S935 may reflect a state marker for G2019S LRRK2-driven PD, the underlying biology for which requires investigation in future studies. This study also provides critical foundational data to inform the integration of pS935 and total LRRK2 levels as biomarkers in therapeutic trials of LRRK2 kinase inhibitors.