ArticleHuman molecular genetics2019
LRRK2 interacts with the vacuolar-type H+-ATPase pump a1 subunit to regulate lysosomal function.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers, 1 of them a synthesis that pooled it.
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Who cites it
76 citing papers in PubMed, 1 synthesis or guideline pooled it, 115 citations in OpenAlex.
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- Leucine-rich repeat kinase 2 (LRRK2): balancing cellular homeostasis and Parkinson's disease (PD) pathogenesis.Annals of medicine · 2026Review
- ATP6V0A1 protects dopaminergic neurons via the autophagy-lysosomal pathway in Parkinson's disease.Neural regeneration research · 2026Article
- Parkinson's disease LRRK2 mutations dysregulate iron homeostasis and promote oxidative stress and ferroptosis in human neurons and astrocytes.Molecular neurodegeneration · 2026Article
- Dysregulation of the TFEB-ATP6V0C axis in microglia exacerbates α-synuclein pathology through impaired lysosomal acidification in Parkinson's disease.Cell death and differentiation · 2026Article
- Oxidative Stress and Lysosomal Dysfunction in Neurodegenerative Diseases: Underlying Mechanisms and Nanotherapeutic Targeting Strategies.Antioxidants (Basel, Switzerland) · 2026Review
- The Fragile Balance: Autophagy's Role in Neurodegenerative Disease Progression.Current neuropharmacology · 2026Review
- One organelle to rule them all: enhancement of lysosomal activity as a therapeutic modality for protein misfolding neurodegenerative diseases.Frontiers in neuroscience · 2026Review
- Review
- The E193K LRRK2 mutation interferes with the autophagosome processing through the impairment of the LRRK2-Dynein-1 complex.Scientific reports · 2025Article
- Role of LRRK2 in axonal transport and Parkinson's disease.The Biochemical journal · 2025Review
- Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2-R1441C rat model of early Parkinson's disease revealed by in vivo PET imaging.Scientific reports · 2025Article
- Article
- Resolving the two-body problem: A postulated role for the V0 sector of the V0V1-ATPase in exosome biogenesis and multivesicular body fate.Molecular biology of the cell · 2025Article
- Roles of LRRK2 and its orthologs in protecting against neurodegeneration and neurodevelopmental defects.Frontiers in cell and developmental biology · 2025Article
- The interplay between physical exercise and autophagy signaling in brain health, neurodegenerative diseases and aging.Frontiers in aging neuroscience · 2025Review
- Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases.Nature reviews. Molecular cell biology · 2024Review
- CK and LRRK2 Involvement in Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- Lysosome quality control in health and neurodegenerative diseases.Cellular & molecular biology letters · 2024Review
- Review
16 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Lysosomal dysfunction lies at the centre of the cellular mechanisms underlying Parkinson's disease although the precise underlying mechanisms remain unknown. We investigated the role of leucine-rich repeat kinase 2 (LRRK2) on lysosome biology and the autophagy pathway in primary neurons expressing the human LRRK2-G2019S or LRKK2-R1441C mutant or the human wild-type (hWT-LRRK2) genomic locus. The expression of LRRK2-G2019S or hWT-LRRK2 inhibited autophagosome production, whereas LRRK2-R1441C induced a decrease in autophagosome/lysosome fusion and increased lysosomal pH. In vivo data from the cortex and substantia nigra pars compacta of aged LRRK2 transgenic animals revealed alterations in autophagosome puncta number reflecting those phenotypes seen in vitro. Using the two selective and potent LRRK2 kinase inhibitors, MLi-2 and PF-06447475, we demonstrated that the LRRK2-R1441C-mediated decrease in autolysosome maturation is not dependent on LRRK2 kinase activity. We showed that hWT-LRRK2 and LRRK2-G2019S bind to the a1 subunit of vATPase, which is abolished by the LRRK2-R1441C mutation, leading to a decrease in a1 protein and cellular mislocalization. Modulation of lysosomal zinc increased vATPase a1 protein levels and rescued the LRRK2-R1441C-mediated cellular phenotypes. Our work defines a novel interaction between the LRRK2 protein and the vATPase a1 subunit and demonstrates a mode of action by which drugs may rescue lysosomal dysfunction. These results demonstrate the importance of LRRK2 in lysosomal biology, as well as the critical role of the lysosome in PD.
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