ArticleExperimental neurology2018
The G2019S mutation in LRRK2 imparts resiliency to kinase inhibition.
Article in Experimental neurology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 46 citations in OpenAlex.
- LRRK2 kinase activity restricts NRF2-dependent mitochondrial protection in microglia.Journal of immunology (Baltimore, Md. : 1950) · 2026Article
- Single molecule array measures of LRRK2 kinase activity in serum link Parkinson's disease severity to peripheral inflammation.Molecular neurodegeneration · 2024Article
- Article
- Inhibition of Parkinson's disease-related LRRK2 by type I and type II kinase inhibitors: Activity and structures.Science advances · 2023Article
- A leucine-rich repeat kinase 2 (LRRK2) pathway biomarker characterization study in patients with Parkinson's disease with and without LRRK2 mutations and healthy controls.Clinical and translational science · 2023Article
- LRRK2-Targeting Therapies March Through the Valley of Death.Movement disorders : official journal of the Movement Disorder Society · 2023Article
- Exploring the focal role of LRRK2 kinase in Parkinson's disease.Environmental science and pollution research international · 2022Review
- Pathological α-synuclein recruits LRRK2 expressing pro-inflammatory monocytes to the brain.Molecular neurodegeneration · 2022Article
- Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein.Acta neuropathologica communications · 2021Article
- Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain.eLife · 2021Article
- LRRK2 Targeting Strategies as Potential Treatment of Parkinson's Disease.Biomolecules · 2021Review
- Genetic background influences LRRK2-mediated Rab phosphorylation in the rat brain.Brain research · 2021Article
- Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons.Journal of Parkinson's disease · 2021Article
- Crohn's and Parkinson's Disease-Associated LRRK2 Mutations Alter Type II Interferon Responses in Human CD14Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2020Article
- Endogenous Rab29 does not impact basal or stimulated LRRK2 pathway activity.The Biochemical journal · 2020Article
- Exosome markers of LRRK2 kinase inhibition.NPJ Parkinson's disease · 2020Article
- LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes.The EMBO journal · 2020Article
- Splice-Switching Antisense Oligonucleotides Reduce LRRK2 Kinase Activity in Human LRRK2 Transgenic Mice.Molecular therapy. Nucleic acids · 2020Article
- Dopaminergic neurodegeneration induced by Parkinson's disease-linked G2019S LRRK2 is dependent on kinase and GTPase activity.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
The G2019S mutation in LRRK2 is one of the most common known genetic causes of neurodegeneration and Parkinson disease (PD). LRRK2 mutations are thought to enhance LRRK2 kinase activity. Efficacious small molecule LRRK2 kinase inhibitors with favorable drug properties have recently been developed for pre-clinical studies in rodent models, and inhibitors have advanced to safety trials in humans. Rats that express human G2019S-LRRK2 protein and G2019S-LRRK2 knock-in mice provide newly characterized models to better understand the ostensible target for inhibitors. Herein, we explore the relationships between LRRK2 kinase inhibition in the brain and the periphery to establish the link between LRRK2 kinase activity and protein stability, induction of lysosomal defects in kidney and lung, and how G2019S-LRRK2 expression impacts these phenotypes. Using a novel ultra-sensitive scalable assay based on protein capillary electrophoresis with LRRK2 kinase inhibitors included in-diet, G2019S-LRRK2 protein was resilient to inhibition compared to wild-type (WT)-LRRK2 protein, particularly in the brain. Whereas WT-LRRK2 kinase activity could be completed blocked without lowering LRRK2 protein levels, higher inhibitor concentrations were necessary to fully reduce G2019S-LRRK2 activity. G2019S-LRRK2 expression afforded robust protection from inhibitor-induced kidney lysosomal defects, suggesting a gain-of-function for the mutation in this phenotype. In rodents treated with inhibitors, parallel measurements of phospho-Rab10 revealed a poor correlation to phospho-LRRK2, likely due to cells that express Rab10 but poorly express LRRK2 in heterogenous tissues and cell isolates. In summary, our results highlight several challenges associated with the inhibition of the G2019S-LRRK2 kinase that might be considered in initial clinical efforts.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.