ArticleeLife2016
Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases.
Article in eLife, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 626 papers.
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Who cites it
626 citing papers in PubMed, 1,052 citations in OpenAlex.
- LRRK2-targeting antisense oligonucleotide in Parkinson's disease: a phase 1 randomized controlled trial.Nature medicine · 2026Trial
- Lipid metabolism dysregulation in Parkinson's disease: A Mendelian randomization and transcriptomic analysis.IBRO neuroscience reports · 2026Article
- Downregulation of prenylation machinery genes in peripheral blood of patients with Parkinson's disease: A pilot study.IBRO neuroscience reports · 2026Article
- Leucine-rich repeat kinase 2 (LRRK2): balancing cellular homeostasis and Parkinson's disease (PD) pathogenesis.Annals of medicine · 2026Review
- ClC-7 links PIKfyve inhibition to Rab-dependent LRRK2 activity at lysosomes.The Journal of cell biology · 2026Article
- Article
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- PPM1H loss alters intrasynaptic alpha-synuclein localization in a LRRK2-dependent manner.Molecular brain · 2026Article
- Subtype-specific secretion of extracellular vesicles by LRRK2 and Rab GTPases under lysosomal stress.iScience · 2026Article
- Mitochondrial Quality Control Imbalance in the Heterogeneity of Parkinson's Disease: From Selective Vulnerability to Stratified Transformation.International journal of molecular sciences · 2026Review
- Parkinson's disease-associated LRRK2 risk variant, G2385R, enhances Rab substrate phosphorylation and impairs neuronal integrity.Human molecular genetics · 2026Article
- Chemical Genetic Targeting of the LRRK2 GTPase Domain.bioRxiv : the preprint server for biology · 2026Article
- Protocol to quantify LRRK2-mediated Rab10 phosphorylation using high-content imaging.STAR protocols · 2026Article
- LRRK2: Molecular Mechanisms in Parkinson's Disease.International journal of molecular sciences · 2026Review
- Review
- Review
- Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons.Nature communications · 2026Article
- Article
- Parkinson's disease LRRK2 mutations dysregulate iron homeostasis and promote oxidative stress and ferroptosis in human neurons and astrocytes.Molecular neurodegeneration · 2026Article
- The LRRK2 G2019S variant rewires Rab GTPase phosphorylation after lysosomal damage and promotes cell death in human macrophages.Journal of cell science · 2026Article
566 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 8 institutions in 3 countries.
Funding
Abstract
Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise the predominant genetic cause of Parkinson's disease (PD). G2019S, the most common amino acid substitution activates the kinase two- to threefold. This has motivated the development of LRRK2 kinase inhibitors; however, poor consensus on physiological LRRK2 substrates has hampered clinical development of such therapeutics. We employ a combination of phosphoproteomics, genetics, and pharmacology to unambiguously identify a subset of Rab GTPases as key LRRK2 substrates. LRRK2 directly phosphorylates these both in vivo and in vitro on an evolutionary conserved residue in the switch II domain. Pathogenic LRRK2 variants mapping to different functional domains increase phosphorylation of Rabs and this strongly decreases their affinity to regulatory proteins including Rab GDP dissociation inhibitors (GDIs). Our findings uncover a key class of bona-fide LRRK2 substrates and a novel regulatory mechanism of Rabs that connects them to PD.
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Registered trials
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.