The Current State-of-the Art of LRRK2-Based Biomarker Assay Development in Parkinson's Disease.

Abstract:

:Evidence is mounting that LRRK2 function, particularly its kinase activity, is elevated in multiple forms of Parkinson's disease, both idiopathic as well as familial forms linked to mutations in the LRRK2 gene. However, sensitive quantitative markers of LRRK2 activation in clinical samples remain at the early stages of development. There are several measures of LRRK2 activity that could potentially be used in longitudinal studies of disease progression, as inclusion/exclusion criteria for clinical trials, to predict response to therapy, or as markers of target engagement. Among these are levels of LRRK2, phosphorylation of LRRK2 itself, either by other kinases or via auto-phosphorylation, its in vitro kinase activity, or phosphorylation of downstream substrates. This is advantageous on many levels, in that multiple indices of elevated kinase activity clearly strengthen the rationale for targeting this kinase with novel therapeutic candidates, and provide alternate markers of activation in certain tissues or biofluids for which specific measures are not detectable. However, this can also complicate interpretation of findings from different studies using disparate measures. In this review we discuss the current state of LRRK2-focused biomarkers, the advantages and disadvantages of the current pallet of outcome measures, the gaps that need to be addressed, and the priorities that the field has defined.

journal_name

Front Neurosci

authors

Rideout HJ,Chartier-Harlin MC,Fell MJ,Hirst WD,Huntwork-Rodriguez S,Leyns CEG,Mabrouk OS,Taymans JM

doi

10.3389/fnins.2020.00865

subject

Has Abstract

pub_date

2020-08-18 00:00:00

pages

865

eissn

1662-4548

issn

1662-453X

journal_volume

14

pub_type

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