ArticleeLife2023
Rab12 is a regulator of LRRK2 and its activation by damaged lysosomes.
Article in eLife, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 42 citations in OpenAlex.
- 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
- LRRK2: Molecular Mechanisms in Parkinson's Disease.International journal of molecular sciences · 2026Review
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- The structural basis for LRRK2's activation and autoinhibition.bioRxiv : the preprint server for biology · 2026Article
- Elucidating the molecular interplay between LRRK2 and Rab GTPases.bioRxiv : the preprint server for biology · 2026Article
- Disruption of the LRRK2 substrate RAB12 facilitates neurotransmission and causes hyperactivity in mice.NPJ Parkinson's disease · 2026Article
- Rab12 is a regulator of mitophagy and mitochondrial homeostasis.bioRxiv : the preprint server for biology · 2026Article
- Axonopathy: mechanisms and potential therapeutic targets for neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Article
- Lysosomal swelling triggers LRRK2 activity.bioRxiv : the preprint server for biology · 2025Article
- LRRK2 integrates Rab and GABARAP interactions to sense and respond to distinct lysosomal stresses.bioRxiv : the preprint server for biology · 2025Article
- JIP4 and RILPL1 utilize opposing motor force to dynamically regulate lysosomal tubulation.The Journal of cell biology · 2025Article
- JIP4 and RILPL1 utilize opposing motor force to dynamically regulate lysosomal tubulation.The Journal of cell biology · 2025Article
- LRRK2 kinase-mediated accumulation of lysosome-associated phospho-Rabs in tauopathies and synucleinopathies.Acta neuropathologica · 2025Article
- Targeting specific kinase substrates rescues increased colitis severity induced by the Crohn's disease-linked LRRK2-N2081D variant.The Journal of clinical investigation · 2025Article
- Targeting specific kinase substrates rescues increased colitis severity induced by the Crohn's disease-linked LRRK2-N2081D variant.The Journal of clinical investigation · 2025Article
- A Common PD-RiskbioRxiv : the preprint server for biology · 2025Article
- PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson's disease.Cell reports · 2025Article
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Leucine-rich repeat kinase 2 (LRRK2) variants associated with Parkinson's disease (PD) and Crohn's disease lead to increased phosphorylation of its Rab substrates. While it has been recently shown that perturbations in cellular homeostasis including lysosomal damage can increase LRRK2 activity and localization to lysosomes, the molecular mechanisms by which LRRK2 activity is regulated have remained poorly defined. We performed a targeted siRNA screen to identify regulators of LRRK2 activity and identified Rab12 as a novel modulator of LRRK2-dependent phosphorylation of one of its substrates, Rab10. Using a combination of imaging and immunopurification methods to isolate lysosomes, we demonstrated that Rab12 is actively recruited to damaged lysosomes and leads to a local and LRRK2-dependent increase in Rab10 phosphorylation. PD-linked variants, including LRRK2 R1441G and VPS35 D620N, lead to increased recruitment of LRRK2 to the lysosome and a local elevation in lysosomal levels of pT73 Rab10. Together, these data suggest a conserved mechanism by which Rab12, in response to damage or expression of PD-associated variants, facilitates the recruitment of LRRK2 and phosphorylation of its Rab substrate(s) at the lysosome.
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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.