ArticleThe Journal of biological chemistry2017
Selective imaging of internalized proteopathic α-synuclein seeds in primary neurons reveals mechanistic insight into transmission of synucleinopathies.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 110 papers.
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Who cites it
110 citing papers in PubMed, 191 citations in OpenAlex.
- Article
- The axonal transport velocity of prions is independent of prion formation.PLoS pathogens · 2026Article
- Flow Cytometric Detection of Biomarker Changes in CFDA-SE-Labelled Plasma Extracellular Vesicles Using a Rodent Pregnancy Model of Prenatal Diagnostics.Journal of extracellular biology · 2026Article
- Determination of α-Synuclein Protein Interactions by μMap Photoproximity Labeling.Journal of the American Chemical Society · 2026Article
- ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Propagation of α-synuclein pathology: models, mechanisms and future goals.Molecular neurodegeneration advances · 2026Review
- Dynein-Dependent Endo-Lysosomal Degradation Drives Lewy Body Disorders Accompanied by Aβ Pathology.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Determination of α-Synuclein Protein Interactions by μMap Photo-proximity Labeling.bioRxiv : the preprint server for biology · 2025Article
- Differential role of C-terminal truncations on alpha-synuclein pathology and Lewy body formation.NPJ Parkinson's disease · 2025Article
- Mechanisms of Alpha-Synuclein-Seeded Aggregation in Neurons Revealed by Fluorescence Lifetime Imaging.ACS chemical neuroscience · 2025Article
- α-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges.International journal of molecular sciences · 2025Review
- Lasting Impact: Exploring the Brain Mechanisms that Link Traumatic Brain Injury to Parkinson's Disease.Molecular neurobiology · 2025Review
- Neuronal constitutive endolysosomal perforations enable α-synuclein aggregation by internalized PFFs.The Journal of cell biology · 2025Article
- Parkinson's disease beyond the brain: implications for treatments.Frontiers in aging neuroscience · 2025Review
- Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons.Molecular neurodegeneration · 2024Article
- MJF-14 proximity ligation assay detects early non-inclusion alpha-synuclein pathology with enhanced specificity and sensitivity.NPJ Parkinson's disease · 2024Article
- Targeting Endogenous Tau in Seeded Tauopathy Models Inhibits Tau Spread.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.Molecular neurodegeneration · 2024Article
- Effects of local reduction of endogenous α-synuclein using antisense oligonucleotides on the fibril-induced propagation of pathology through the neural network in wild-type mice.Acta neuropathologica communications · 2024Article
- O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology.Nature chemical biology · 2024Article
50 more citing papers are in PubMed but not listed here.
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6 authors at 2 institutions in 1 country.
Funding
Abstract
Direct cell-to-cell transmission of proteopathic α-synuclein (α-syn) aggregates is thought to underlie the progression of neurodegenerative synucleinopathies. However, the specific intracellular processes governing this transmission remain unclear because currently available model systems are limited. For example, in cell culture models of α-syn-seeded aggregation, it is difficult to discern intracellular from extracellular exogenously applied α-syn seed species. Herein, we employed fluorescently labeled α-syn preformed fibrils (pffs) in conjunction with the membrane-impermeable fluorescence quencher trypan blue to selectively image internalized α-syn seeds in cultured primary neurons and to quantitatively characterize the concentration dependence, time course, and inhibition of pff uptake. To study the long-term fates of exogenous α-syn pffs in neurons, we developed a pff species labeled at amino acid residue 114 with the environmentally insensitive fluorophore BODIPY or the pH-sensitive dye pHrodo red. We found that pffs are rapidly trafficked along the endolysosomal pathway, where most of the material remains for days. We also found that brief pharmacological perturbation of lysosomes shortly after the pff treatment causes aberrations in intracellular processing of pff seeds concomitant with an increased rate of inclusion formation via recruitment of endogenous α-syn to a relatively small number of exogenous seeds. Our results validate a quantitative assay for pff uptake in primary neurons, implicate lysosomal processing as the major fate of internalized proteopathic seeds, and suggest lysosomal integrity as a significant rate-determining step in the transmission of α-syn pathology. Further, lysosomal processing of transmitted seeds may represent a new therapeutic target to combat the spread of synucleinopathies.
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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.