ArticleiScience2024
Lysosomal stress drives the release of pathogenic α-synuclein from macrophage lineage cells via the LRRK2-Rab10 pathway.
Article in iScience, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 14 citations in OpenAlex.
- Subtype-specific secretion of extracellular vesicles by LRRK2 and Rab GTPases under lysosomal stress.iScience · 2026Article
- The LRRK2 G2019S variant rewires Rab GTPase phosphorylation after lysosomal damage and promotes cell death in human macrophages.Journal of cell science · 2026Article
- Calcineurin/NFAT signaling in the temporal integration of Ca²⁺ stress in neurodegeneration.Cell death discovery · 2026Review
- Nuclear dysfunction in aging and neurodegeneration.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- Using iPSC models to examine neuron-glia interactions in neurodegenerative diseases.Bioscience reports · 2026Review
- The emerging role and therapeutic targeting of autophagy-lysosome pathway in the pathogenesis of Parkinson's disease.Translational neurodegeneration · 2026Review
- Targeting the secretory autophagy-extracellular vesicle interface: fate decisions and translational opportunities.Frontiers in pharmacology · 2026Review
- Propagation of α-synuclein pathology: models, mechanisms and future goals.Molecular neurodegeneration advances · 2026Review
- RNA networks of lysosomal-related biomarkers in Parkinson's disease and their correlations with freezing of gait-associated genes.Frontiers in genetics · 2026Article
- Integrated Biofluid Proteomics Identified Dynamic Functional Biomarkers ofmedRxiv : the preprint server for health sciences · 2025Article
- Underlying Mechanisms of GBA1 in Parkinson's Disease and Dementia with Lewy Bodies: Narrative Review.Genes · 2025Review
- LRRK2 and the fragile synapse: a molecular prelude to Parkinson's disease?The Biochemical journal · 2025Review
- Rab27b Promotes Lysosomal Function and Alpha-Synuclein Clearance in Neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Canonical and noncanonical autophagy: involvement in Parkinson's disease.Frontiers in cell and developmental biology · 2025Review
- Lysosomes' fallback strategies: more than just survival or death.Frontiers in cell and developmental biology · 2025Review
- The role of autophagy in synucleinopathy: clearance versus spread of α-synuclein.Autophagy reports · 2025Review
- Emerging role of microglia in inter-cellular transmission of α-synuclein in Parkinson's disease.Frontiers in aging neuroscience · 2024Review
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
α-Synuclein and LRRK2 are associated with both familial and sporadic Parkinson's disease (PD), although the mechanistic link between these two proteins has remained elusive. Treating cells with lysosomotropic drugs causes the recruitment of LRRK2 and its substrate Rab10 onto overloaded lysosomes and induces extracellular release of lysosomal contents. Here we show that lysosomal overload elicits the release of insoluble α-synuclein from macrophages and microglia loaded with α-synuclein fibrils. This release occurred specifically in macrophage lineage cells, was dependent on the LRRK2-Rab10 pathway and involved exosomes. Also, the uptake of α-synuclein fibrils enhanced the LRRK2 phosphorylation of Rab10, which was accompanied by an increased recruitment of LRRK2 and Rab10 onto lysosomal surface. Our data collectively suggest that α-synuclein fibrils taken up in lysosomes activate the LRRK2-Rab10 pathway, which in turn upregulates the extracellular release of α-synuclein aggregates, leading to a vicious cycle that could enhance α-synuclein propagation in PD pathology.
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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.