Inhibitor treatment of peripheral mononuclear cells from Parkinson's disease patients further validates LRRK2 dephosphorylation as a pharmacodynamic biomarker

G. Perera, M. Ranola, D. B. Rowe, G. M. Halliday, N. Dzamko*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    29 Citations (Scopus)
    105 Downloads (Pure)

    Abstract

    Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with increased risk of Parkinson's disease (PD). Thus, LRRK2 kinase inhibitors are in development as potential Parkinson's disease therapeutics. A reduction in the constitutive levels of phosphorylation on leucine-rich repeat kinase 2 (LRRK2) is currently used to measure target engagement of LRRK2 kinase inhibitors in cell and animal models. We aimed to determine if reduced phosphorylation of LRRK2 following inhibitor treatment is also a valid measure of target engagement in peripheral mononuclear cells from Parkinson's disease patients. Peripheral mononuclear cells from idiopathic Parkinson's disease patients and controls were treated ex vivo with two structurally distinct inhibitors of LRRK2, at four different doses, and immunoblotting was used to assess the reduction in LRRK2 phosphorylation at Ser910, Ser935, Ser955 and Ser973. Both inhibitors showed no acute toxicity in primary cells and both inhibitors reduced the constitutive phosphorylation of LRRK2 at all measured residues equally in both control and Parkinson's disease groups. Measuring the reduction in LRRK2 phosphorylation resulting from LRRK2 kinase inhibition, is thus a valid measure of acute peripheral target engagement in Parkinson's disease patients. This is important if LRRK2 kinase inhibitors are to be used in a clinical setting.

    Original languageEnglish
    Article number31391
    Pages (from-to)1-8
    Number of pages8
    JournalScientific Reports
    Volume6
    DOIs
    Publication statusPublished - 9 Aug 2016

    Bibliographical note

    Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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