An Assessment of LRRK2 Serine 935 Phosphorylation in Human Peripheral Blood Mononuclear Cells in Idiopathic Parkinson's Disease and G2019S LRRK2 Cohorts

Shalini Padmanabhan, Thomas A. Lanz, Donal Gorman, Michele Wolfe, Alison Joyce, Carlos Cabrera, Rosemary Lawrence-Henderson, Najah Levers, Neal Joshi, Thong C. Ma, Christopher Liong, Sushma Narayan, Roy N. Alcalay, Samantha J. Hutten, Marco A.S. Baptista, Kalpana Merchant*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 controls, 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.

Original languageEnglish
Pages (from-to)623-629
Number of pages7
JournalJournal of Parkinson's Disease
Volume10
Issue number2
DOIs
StatePublished - 2020
Externally publishedYes

Funding

FundersFunder number
Parkinson’s Foundation
National Institutes of Health
Michael J. Fox Foundation for Parkinson's Research
Pfizer

    Keywords

    • biomarker
    • blood cells
    • Parkinson's disease
    • pharmacodynamic

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