<scp>LRRK2</scp>‐Targeting Therapies March Through the Valley of Death

West, Andrew B.; Schwarzschild, Michael A.

doi:10.1002/mds.29343

Cited by 4 publications

(1 citation statement)

References 37 publications

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“…In genome-wide association studies, the rs76904798 variant in the LRRK2 promoter increases iPD risk, independent of LRRK2 missense mutations, while the LRRK2 N551K/R1398H allele may decrease iPD risk [3,4]. The role of LRRK2 in disease progression in iPD is not clear [5]. Biomarkers for LRRK2 activity, as they may reflect different disease states or change with disease progression, could provide insights into the role of LRRK2 in disease progression.…”

Section: Introductionmentioning

confidence: 99%

Single molecule array measures of LRRK2 kinase activity in serum link Parkinson’s disease severity to peripheral inflammation

Yuan,

Li,

Sreeram

et al. 2024

Preprint

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Background: LRRK2-targeting therapeutics that inhibit LRRK2 kinase activity have advanced to clinical trials in idiopathic Parkinson's disease (iPD). LRRK2 phosphorylates Rab10 on endolysosomes in phagocytic cells to promote some types of immunological responses. The identification of factors that regulate LRRK2-mediated Rab10 phosphorylation in iPD, and whether phosphorylated-Rab10 levels change in different disease states, or with disease progression, may provide insights into the role of Rab10 phosphorylation in iPD and help guide therapeutic strategies targeting this pathway. Methods: Capitalizing on past work demonstrating LRRK2 and phosphorylated-Rab10 interact on vesicles that can shed into biofluids, we developed and validated a high-throughput single-molecule array assay to measure extracellular pT73-Rab10. Ratios of pT73-Rab10 to total Rab10 measured in biobanked serum samples were compared between informative groups of transgenic mice, rats, and a deeply phenotyped cohort of iPD cases and controls. Multivariable and weighted correlation network analyses were used to identify genetic, transcriptomic, clinical, and demographic variables that predict the extracellular pT73-Rab10 to total Rab10 ratio. Results: pT73-Rab10 is absent in serum from Lrrk2 knockout mice but elevated by LRRK2 and VPS35 mutations, as well as SNCA expression. Bone-marrow transplantation experiments in mice show that serum pT73-Rab10 levels derive primarily from circulating immune cells. The extracellular ratio of pT73-Rab10 to total Rab10 is dynamic, increasing with inflammation and rapidly decreasing with LRRK2 kinase inhibition. The ratio of pT73-Rab10 to total Rab10 is elevated in iPD patients with greater motor dysfunction, irrespective of disease duration, age, sex, or the usage of PD-related or anti-inflammatory medications. pT73-Rab10 to total Rab10 ratios are associated with neutrophil activation, antigenic responses, and the suppression of platelet activation. Conclusions: The extracellular ratio of pT73-Rab10 to total Rab10 in serum is a novel pharmacodynamic biomarker for LRRK2-linked innate immune activation associated with disease severity in iPD. We propose that those iPD patients with higher serum pT73-Rab10 levels may benefit from LRRK2-targeting therapeutics to mitigate associated deleterious immunological responses.

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Section: Introductionmentioning

confidence: 99%

Single molecule array measures of LRRK2 kinase activity in serum link Parkinson’s disease severity to peripheral inflammation

Yuan,

Li,

Sreeram

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting

Xiong,

2024

Trends in Molecular Medicine

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Single molecule array measures of LRRK2 kinase activity in serum link Parkinson’s disease severity to peripheral inflammation

Yuan,

Li,

Sreeram

et al. 2024

Mol Neurodegeneration

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Background LRRK2-targeting therapeutics that inhibit LRRK2 kinase activity have advanced to clinical trials in idiopathic Parkinson’s disease (iPD). LRRK2 phosphorylates Rab10 on endolysosomes in phagocytic cells to promote some types of immunological responses. The identification of factors that regulate LRRK2-mediated Rab10 phosphorylation in iPD, and whether phosphorylated-Rab10 levels change in different disease states, or with disease progression, may provide insights into the role of Rab10 phosphorylation in iPD and help guide therapeutic strategies targeting this pathway. Methods Capitalizing on past work demonstrating LRRK2 and phosphorylated-Rab10 interact on vesicles that can shed into biofluids, we developed and validated a high-throughput single-molecule array assay to measure extracellular pT73-Rab10. Ratios of pT73-Rab10 to total Rab10 measured in biobanked serum samples were compared between informative groups of transgenic mice, rats, and a deeply phenotyped cohort of iPD cases and controls. Multivariable and weighted correlation network analyses were used to identify genetic, transcriptomic, clinical, and demographic variables that predict the extracellular pT73-Rab10 to total Rab10 ratio. Results pT73-Rab10 is absent in serum from Lrrk2 knockout mice but elevated by LRRK2 and VPS35 mutations, as well as SNCA expression. Bone-marrow transplantation experiments in mice show that serum pT73-Rab10 levels derive primarily from circulating immune cells. The extracellular ratio of pT73-Rab10 to total Rab10 is dynamic, increasing with inflammation and rapidly decreasing with LRRK2 kinase inhibition. The ratio of pT73-Rab10 to total Rab10 is elevated in iPD patients with greater motor dysfunction, irrespective of disease duration, age, sex, or the usage of PD-related or anti-inflammatory medications. pT73-Rab10 to total Rab10 ratios are associated with neutrophil degranulation, antigenic responses, and suppressed platelet activation. Conclusions The extracellular serum ratio of pT73-Rab10 to total Rab10 is a novel pharmacodynamic biomarker for LRRK2-linked innate immune activation associated with disease severity in iPD. We propose that those iPD patients with higher serum pT73-Rab10 levels may benefit from LRRK2-targeting therapeutics that mitigate associated deleterious immunological responses.

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LRRK2‐Targeting Therapies March Through the Valley of Death

Cited by 4 publications

References 37 publications

Single molecule array measures of LRRK2 kinase activity in serum link Parkinson’s disease severity to peripheral inflammation

Single molecule array measures of LRRK2 kinase activity in serum link Parkinson’s disease severity to peripheral inflammation

LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting

Single molecule array measures of LRRK2 kinase activity in serum link Parkinson’s disease severity to peripheral inflammation

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