ArticleThe Biochemical journal2021
Development of a multiplexed targeted mass spectrometry assay for LRRK2-phosphorylated Rabs and Ser910/Ser935 biomarker sites.
Article in The Biochemical journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 46 citations in OpenAlex.
- Leucine-rich repeat kinase 2 (LRRK2): balancing cellular homeostasis and Parkinson's disease (PD) pathogenesis.Annals of medicine · 2026Review
- Addressing the Challenges of Translating LRRK2 Biology into Disease-Modifying Therapies: The LRRK2 Investigative Therapeutics Exchange Initiative.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Article
- BLTP3A is associated with membranes of the late endocytic pathway and is an effector of CASM.The EMBO journal · 2025Article
- Selectivity profiles and substrate recognition of Rab-phosphorylating kinases.The Biochemical journal · 2025Article
- 14-3-3 binding maintains the Parkinson's associated kinase LRRK2 in an inactive state.Nature communications · 2025Article
- Inflammation and IL-4 regulate Parkinson's and Crohn's disease associated kinase LRRK2.EMBO reports · 2025Article
- Leucine-rich repeat kinase 2 biomarkers for Parkinson's disease.The Biochemical journal · 2025Review
- Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- A RAB7A phosphoswitch coordinates Rubicon Homology protein regulation of Parkin-dependent mitophagy.The Journal of cell biology · 2024Article
- Single molecule array measures of LRRK2 kinase activity in serum link Parkinson's disease severity to peripheral inflammation.Molecular neurodegeneration · 2024Article
- G2019S selective LRRK2 kinase inhibitor abrogates mitochondrial DNA damage.NPJ Parkinson's disease · 2024Article
- A potential patient stratification biomarker for Parkinson´s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells.NPJ Parkinson's disease · 2024Article
- Parkinson's VPS35[D620N] mutation induces LRRK2-mediated lysosomal association of RILPL1 and TMEM55B.Science advances · 2023Article
- Review
- Structure of LRRK1 and mechanisms of autoinhibition and activation.Nature structural & molecular biology · 2023Article
- Whole proteome copy number dataset in primary mouse cortical neurons.Data in brief · 2023Article
- Insights into the cellular consequences of LRRK2-mediated Rab protein phosphorylation.Biochemical Society transactions · 2023Review
- Protein aggregation and calcium dysregulation are hallmarks of familial Parkinson's disease in midbrain dopaminergic neurons.NPJ Parkinson's disease · 2022Article
- PKC isoforms activate LRRK1 kinase by phosphorylating conserved residues (Ser1064, Ser1074 and Thr1075) within the CORB GTPase domain.The Biochemical journal · 2022Article
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Mutations that increase the protein kinase activity of LRRK2 are one of the most common causes of familial Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif, impacting interaction with effectors. We describe and validate a new, multiplexed targeted mass spectrometry assay to quantify endogenous levels of LRRK2-phosphorylated Rab substrates (Rab1, Rab3, Rab8, Rab10, Rab35 and Rab43) as well as total levels of Rabs, LRRK2 and LRRK2-phosphorylated at the Ser910 and Ser935 biomarker sites. Exploiting this assay, we quantify for the first time the relative levels of each of the pRab proteins in different cells (mouse embryonic fibroblasts, human neutrophils) and mouse tissues (brain, kidney, lung and spleen). We define how these components are impacted by Parkinson's pathogenic mutations (LRRK2[R1441C] and VPS35[D620N]) and LRRK2 inhibitors. We find that the VPS35[D620N], but not LRRK2[R1441C] mutation, enhances Rab1 phosphorylation in a manner blocked by administration of an LRRK2 inhibitor, providing the first evidence that endogenous Rab1 is a physiological substrate for LRRK2. We exploit this assay to demonstrate that in Parkinson's patients with VPS35[D620N] mutations, phosphorylation of multiple Rab proteins (Rab1, Rab3, Rab8, Rab10 and Rab43) is elevated. We highlight the benefits of this assay over immunoblotting approaches currently deployed to assess LRRK2 Rab signalling pathway.
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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.