ArticleMolecular neurodegeneration2014
Vacuolar protein sorting 35 (Vps35) rescues locomotor deficits and shortened lifespan in Drosophila expressing a Parkinson's disease mutant of Leucine-Rich Repeat Kinase 2 (LRRK2).
Article in Molecular neurodegeneration, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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58 citing papers in PubMed, 111 citations in OpenAlex.
- Retromer-targeted therapy for neurodegenerative diseases.Molecular neurodegeneration · 2026Review
- Vacuolar protein sorting 35 regulates retinal neurovascular functionInternational journal of ophthalmology · 2026Article
- Proteome Profiling of Rabies-Infected and Uninfected Dog Brain Tissues, Cerebrospinal Fluids and Serum Samples.Proteomes · 2025Article
- Retromer promotes the lysosomal turnover of mtDNA.Science advances · 2025Article
- LRRK2 in Drosophila Melanogaster Model: Insights into Cellular Dysfunction and Neuroinflammation in Parkinson's Disease.International journal of molecular sciences · 2025Review
- VPS35 or retromer as a potential target for neurodegenerative disorders: barriers to progress.Expert opinion on therapeutic targets · 2024Review
- Strategies for modeling aging and age-related diseases.npj aging · 2024Review
- Dysregulation of SNX1-retromer axis in pharmacogenetic models of Parkinson's disease.Cell death discovery · 2024Article
- LRK-1/LRRK2 and AP-3 regulate trafficking of synaptic vesicle precursors through active zone protein SYD-2/Liprin-α.PLoS genetics · 2024Article
- VPS35 and retromer dysfunction in Parkinson's disease.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- Retromer-dependent lysosomal stress in Parkinson's disease.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine physiology in VPS35 p.D620N knock-in mice.NPJ Parkinson's disease · 2023Article
- Parkinson disease-associated Leucine-rich repeat kinase regulates UNC-104-dependent axonal transport of Arl8-positive vesicles iniScience · 2022Article
- Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA.Nature communications · 2022Article
- Understanding the contributions of VPS35 and the retromer in neurodegenerative disease.Neurobiology of disease · 2022Review
- Polarized α-synuclein trafficking and transcytosis across brain endothelial cells via Rab7-decorated carriers.Fluids and barriers of the CNS · 2022Article
- The understudied links of the retromer complex to age-related pathways.GeroScience · 2022Article
- Beware of Misdelivery: Multifaceted Role of Retromer Transport in Neurodegenerative Diseases.Frontiers in aging neuroscience · 2022Review
- Pathogenic LRRK2 control of primary cilia and Hedgehog signaling in neurons and astrocytes of mouse brain.eLife · 2021Article
- Endosomal traffic and glutamate synapse activity are increased in VPS35 D620N mutant knock-in mouse neurons, and resistant to LRRK2 kinase inhibition.Molecular brain · 2021Article
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundParkinson's disease (PD) is the most common movement neurodegenerative movement disorder. An incomplete understanding of the molecular pathways involved in its pathogenesis impedes the development of effective disease-modifying treatments. To address this gap, we have previously generated a Drosophila model of PD that overexpresses PD pathogenic mutant form of the second most common causative gene of PD, Leucine-Rich Repeat Kinase 2 (LRRK2).
findingsWe employed this model in a genetic modifier screen and identified a gene that encodes for a core subunit of retromer - a complex essential for the sorting and recycling of specific cargo proteins from endosomes to the trans-Golgi network and cell surface. We present evidence that overexpression of the Vps35 or Vps26 component of the cargo-recognition subunit of the retromer complex ameliorates the pathogenic mutant LRRK2 eye phenotype. Furthermore, overexpression of Vps35 or Vps26 significantly protects from the locomotor deficits observed in mutant LRRK2 flies, as assessed by the negative geotaxis assay, and rescues their shortened lifespan. Strikingly, overexpressing Vps35 alone protects from toxicity of rotenone, a neurotoxin commonly used to model parkinsonism, both in terms of lifespan and locomotor activity of the flies, and this protection is sustained and even augmented in the presence of mutant LRRK2. Finally, we demonstrate that knocking down expression of Vps35 in dopaminergic neurons causes a significant locomotor impairment.
conclusionsFrom these results we conclude that LRRK2 plays a role in the retromer pathway and that this pathway is involved in PD pathogenesis.
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