ArticleThe Biochemical journal2024
The Parkinson's disease related mutant VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress.
Article in The Biochemical journal, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 7 citations in OpenAlex.
- ClC-7 links PIKfyve inhibition to Rab-dependent LRRK2 activity at lysosomes.The Journal of cell biology · 2026Article
- Roles of autophagy in brain homeostasis and disease.Nature neuroscience · 2026Review
- In vivo Proximity & Spatial Proteomics with CRISPR Screening Identify STXBP1 as a Protective Modifier of α-synuclein Toxicity in Dopamine Neurons.bioRxiv : the preprint server for biology · 2026Article
- Vacuolar protein sorting 35 regulates retinal neurovascular functionInternational journal of ophthalmology · 2026Article
- LRRK2 integrates Rab and GABARAP interactions to sense and respond to distinct lysosomal stresses.bioRxiv : the preprint server for biology · 2025Article
- Role of LRRK2 in axonal transport and Parkinson's disease.The Biochemical journal · 2025Review
- LRRK2 in Drosophila Melanogaster Model: Insights into Cellular Dysfunction and Neuroinflammation in Parkinson's Disease.International journal of molecular sciences · 2025Review
- Mechanisms of lysosomal tubulation and sorting driven by LRRK2.Biochemical Society transactions · 2024Review
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The identification of multiple genes linked to Parkinson's disease (PD) invites the question as to how they may co-operate. We have generated isogenic cell lines that inducibly express either wild-type or a mutant form of the retromer component VPS35 (D620N), which has been linked to PD. This has enabled us to test proposed effects of this mutation in a setting where the relative expression reflects the physiological occurrence. We confirm that this mutation compromises VPS35 association with the WASH complex, but find no defect in WASH recruitment to endosomes, nor in the distribution of lysosomal receptors, cation-independent mannose-6-phosphate receptor and Sortilin. We show VPS35 (D620N) enhances the activity of the Parkinson's associated kinase LRRK2 towards RAB12 under basal conditions. Furthermore, VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress resulting in enhanced phosphorylation of RABs 10 and 12. By comparing different types of endolysosomal stresses such as the ionophore nigericin and the membranolytic agent l-leucyl-l-leucine methyl ester, we are able to dissociate phospho-RAB accumulation from membrane rupture.
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