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.
Highlights
Parkinson’s disease (PD) is a debilitating neurodegenerative disorder, affecting millions of people worldwide
Assuming that environmental factors may have a larger impact on sporadic PD development compared to familial PD, it is surprising that no difference is found between sporadic PD and leucine-rich repeat kinase 2 (LRRK2) patients heterozygous for a LRRK2 mutation either in the methylation status of islands of the LRRK2 promoter in patient derived leucocytes (Fernandez-Santiago et al, 2015) or when investigating whole genome methylation of dopaminergic neurons generated from patient derived induced pluripotent stem cells
We have summarized the current state of biomarker development and use in Table 1, and key outstanding issues are highlighted in Box 1
Summary
Parkinson’s disease (PD) is a debilitating neurodegenerative disorder, affecting millions of people worldwide. A link has been postulated between LRRK2 and GCase activity (Alcalay et al, 2015; Nguyen and Krainc, 2018); some controversy still exists concerning the nature of this link Given these links as well as the prevalence of LRRK2 risk variants in the sporadic PD population, there is significant evidence supporting the therapeutic potential of LRRK2 inhibition in sporadic PD as well as additional familial PD cohorts beyond LRRK2 mutation carriers. There are several measures of LRRK2 function that could potentially be used in longitudinal studies of disease progression, as inclusion/exclusion criteria for clinical trials, as markers of target engagement, and as markers to predict response to therapy Among these are levels of LRRK2, phosphorylation of LRRK2, either by other kinases or via auto-phosphorylation, in vitro LRRK2 kinase activity, and phosphorylation of downstream substrates or functional endpoints related to elevated (or therapeutic suppression of) LRRK2 function, which will be covered in this review. Multiple kinases have been implicated in the phosphorylation of these residues, including: CK1-α1 (Chia et al, 2014),
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