ArticleScience advances2023
Parkinson's VPS35[D620N] mutation induces LRRK2-mediated lysosomal association of RILPL1 and TMEM55B.
Article in Science advances, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 31 papers.
What it found
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Who cites it
31 citing papers in PubMed, 34 citations in OpenAlex.
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- Retromer-targeted therapy for neurodegenerative diseases.Molecular neurodegeneration · 2026Review
- LRRK2: Molecular Mechanisms in Parkinson's Disease.International journal of molecular sciences · 2026Review
- ATP6V0A1 protects dopaminergic neurons via the autophagy-lysosomal pathway in Parkinson's disease.Neural regeneration research · 2026Article
- VPS35 mutation inhibits PINK1/parkin-mediated mitophagy via increased LRRK2 kinase activity.Brain : a journal of neurology · 2026Article
- The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair.The EMBO journal · 2026Article
- Targeting of kinases to treat neurodegenerative diseases.Pharmacological reviews · 2026Review
- Control of lysosome function by the GTPase-activating protein TBC1D9B and its binding partner TMEM55B.Nature communications · 2026Article
- Subcellular Cartography of the Phosphoinositide Multiverse.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2026Review
- Rab8a dysregulation in Parkinson's disease: A convergence of genetic and molecular pathologies.Molecular biology reports · 2026Review
- Mass spectrometry imaging tutorial: From cancer biomarker discovery to clinical applications.Analytica chimica acta · 2026Review
- Sources of Oxidative Stress in Parkinson's Disease: Pathways and Therapeutic Implications.Antioxidants (Basel, Switzerland) · 2026Review
- Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.Autophagy · 2026Review
- Autophagy-Lysosome Pathway Dysfunction in Neurodegeneration and Cancer: Mechanisms and Therapeutic Opportunities.International journal of molecular sciences · 2025Review
- JIP4 and RILPL1 utilize opposing motor force to dynamically regulate lysosomal tubulation.The Journal of cell biology · 2025Article
- TMEM55A-mediated PI5P signalling regulates alpha cell actin depolymerisation and glucagon secretion.Diabetologia · 2025Article
- Role of LRRK2 in axonal transport and Parkinson's disease.The Biochemical journal · 2025Review
- JIP4 deficiency causes a lysosomal storage disease arising from impaired cystine efflux.bioRxiv : the preprint server for biology · 2025Article
- Leucine-Rich Repeat Kinase 1 Signaling Targets Proteins Critical for Endosome/Lysosome Sorting and Trafficking in Osteoclasts.Biology · 2025Article
- Immune cell metabolic dysfunction in Parkinson's disease.Molecular neurodegeneration · 2025Review
Corrections and comments
- Erratum issued
Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
Abstract
We demonstrate that the Parkinson's VPS35[D620N] mutation alters the expression of ~220 lysosomal proteins and stimulates recruitment and phosphorylation of Rab proteins at the lysosome. This recruits the phospho-Rab effector protein RILPL1 to the lysosome where it binds to the lysosomal integral membrane protein TMEM55B. We identify highly conserved regions of RILPL1 and TMEM55B that interact and design mutations that block binding. In mouse fibroblasts, brain, and lung, we demonstrate that the VPS35[D620N] mutation reduces RILPL1 levels, in a manner reversed by LRRK2 inhibition and proteasome inhibitors. Knockout of RILPL1 enhances phosphorylation of Rab substrates, and knockout of TMEM55B increases RILPL1 levels. The lysosomotropic agent LLOMe also induced LRRK2 kinase-mediated association of RILPL1 to the lysosome, but to a lower extent than the D620N mutation. Our study uncovers a pathway through which dysfunctional lysosomes resulting from the VPS35[D620N] mutation recruit and activate LRRK2 on the lysosomal surface, driving assembly of the RILPL1-TMEM55B complex.
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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.