ArticleThe Journal of cell biology2025
Neuronal constitutive endolysosomal perforations enable α-synuclein aggregation by internalized PFFs.
Article in The Journal of cell biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Astrocytes mobilize a broader repertoire of lysosomal repair mechanisms than neurons.iScience · 2026Article
- Article
- Modeling Parkinson's pathology in human iPSC dopaminergic neurons uncovers key mechanisms of Lewy body formation and heterogeneity.Science advances · 2026Article
- Naked antisense oligonucleotides remain endolysosomally sequestered despite induced membrane damage.bioRxiv : the preprint server for biology · 2026Article
- Axonopathy: mechanisms and potential therapeutic targets for neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Alpha-Synuclein in Neurodegeneration: From Shared Biology to Disease-Specific Phenotypes.Cells · 2026Review
- Seeing the Unseen: Super-Resolution Microscopy in Protein Aggregation Research.Chemical & biomedical imaging · 2026Review
- Close-up of vesicular ER exit sites by volume electron imaging using FIB-SEM.The Journal of cell biology · 2026Article
- Review
- Tau seeding in neurons enabled by transient endolysosomal perforations are confined within endolysosomes.bioRxiv : the preprint server for biology · 2025Article
- Lysosome heterogeneity and diversity mapped through its distinct cellular functions.Cellular and molecular life sciences : CMLS · 2025Review
- Potential Role of Membrane Contact Sites in the Dysregulation of the Crosstalk Between Mitochondria and Lysosomes in Alzheimer's Disease.International journal of molecular sciences · 2025Review
- Single-vesicle Tracking of α-Synuclein Oligomers Reveals Pore Formation by a Three-Stage Model.ACS nano · 2025Article
- Molecular Visualization of Neuronal TDP43 PathologybioRxiv : the preprint server for biology · 2025Article
- Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases.Cells · 2025Review
- Article
- Proteostasis and lysosomal repair deficits in transdifferentiated neurons of Alzheimer's disease.Nature cell biology · 2025Article
- Harnessing lysohormesis for healthy ageing.Nature cell biology · 2025Article
- The spectrum of lysosomal stress and damage responses: from mechanosensing to inflammation.EMBO reports · 2025Review
- Intercellular transmission of alpha-synuclein.Frontiers in molecular neuroscience · 2024Review
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Abstract
Endocytosis, required for the uptake of receptors and their ligands, can also introduce pathological aggregates such as α-synuclein (α-syn) in Parkinson's Disease. We show here the unexpected presence of intrinsically perforated endolysosomes in neurons, suggesting involvement in the genesis of toxic α-syn aggregates induced by internalized preformed fibrils (PFFs). Aggregation of endogenous α-syn in late endosomes and lysosomes of human iPSC-derived neurons (iNs), seeded by internalized α-syn PFFs, caused the death of the iNs but not of the parental iPSCs and non-neuronal cells. Live-cell imaging of iNs showed constitutive perforations in ∼5% of their endolysosomes. These perforations, identified by 3D electron microscopy in iNs and CA1 pyramidal neurons and absent in non-neuronal cells, may facilitate cytosolic access of endogenous α-syn to PFFs in the lumen of endolysosomes, triggering aggregation. Inhibiting the PIKfyve phosphoinositol kinase reduced α-syn aggregation and associated iN death, even with ongoing PFF endolysosomal entry, suggesting that maintaining endolysosomal integrity might afford a therapeutic strategy to counteract synucleinopathies.
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