ArticleThe Journal of biological chemistry2020
Fibrillar α-synuclein toxicity depends on functional lysosomes.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 56 citations in OpenAlex.
- Preformed fibrils of α-synuclein rapidly activate LRRK2 on early endosomes, driving Rab5 phosphorylation and disrupting endolysosomal and synaptic function.NPJ Parkinson's disease · 2026Article
- Microengineering of the capillary interface of midbrain dopaminergic neurons to study Parkinson's disease vascular alterations.Communications engineering · 2026Article
- Towards a Biologically Defined Diagnosis: Incorporating Pathophysiological Measures Into Parkinson's Disease Clinical Criteria.Parkinson's disease · 2026Review
- Liproxstatin-1 Protects SH-SY5Y Cells by Inhibiting HInternational journal of molecular sciences · 2025Article
- DDOX expands the repertoire of tetracyclines for Parkinson's disease by preventing the cellular uptake and intracellular impact of α-synuclein preformed fibrils.Scientific reports · 2025Article
- Article
- Emerging Links Between Ferroptosis and Neurodegeneration: Implications for Disease Mechanisms and Nutraceutical Interventions.Food science & nutrition · 2025Review
- The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.Molecular neurodegeneration · 2024Article
- Exploring α-synuclein Interaction Partners and their Potential Clinical Implications for Parkinson's Disease.Neurochemical research · 2024Article
- The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.Research square · 2024Article
- The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.bioRxiv : the preprint server for biology · 2023Article
- Animal models of Parkinson's disease: bridging the gap between disease hallmarks and research questions.Translational neurodegeneration · 2023Review
- Evaluating the mouse neural precursor line, SN4741, as a suitable proxy for midbrain dopaminergic neurons.BMC genomics · 2023Article
- Distinct Effects of Familial Parkinson's Disease-Associated Mutations on α-Synuclein Phase Separation and Amyloid Aggregation.Biomolecules · 2023Article
- HTT (huntingtin) and RAB7 co-migrate retrogradely on a signaling LAMP1-containing late endosome during axonal injury.Autophagy · 2023Article
- Alpha Synuclein: Neurodegeneration and Inflammation.International journal of molecular sciences · 2023Review
- Role of α-synuclein in microglia: autophagy and phagocytosis balance neuroinflammation in Parkinson's disease.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2023Review
- Evaluating the mouse neural precursor line, SN4741, as a suitable proxy for midbrain dopaminergic neurons.Research square · 2023Article
- Evaluating the mouse neural precursor line, SN4741, as a suitable proxy for midbrain dopaminergic neurons.bioRxiv : the preprint server for biology · 2023Article
- Aggregation of alpha-synuclein in enteric neurons does not impact function in vitro.Scientific reports · 2022Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Neurodegeneration in Parkinson's disease (PD) can be recapitulated in animals by administration of α-synuclein preformed fibrils (PFFs) into the brain. However, the mechanism by which these PFFs induce toxicity is unknown. Iron is implicated in PD pathophysiology, so we investigated whether α-synuclein PFFs induce ferroptosis, an iron-dependent cell death pathway. A range of ferroptosis inhibitors were added to a striatal neuron-derived cell line (STHdhQ7/7 cells), a dopaminergic neuron-derived cell line (SN4741 cells), and WT primary cortical neurons, all of which had been intoxicated with α-synuclein PFFs. Viability was not recovered by these inhibitors except for liproxstatin-1, a best-in-class ferroptosis inhibitor, when used at high doses. High-dose liproxstatin-1 visibly enlarged the area of a cell that contained acidic vesicles and elevated the expression of several proteins associated with the autophagy-lysosomal pathway similarly to the known lysosomal inhibitors, chloroquine and bafilomycin A1. Consistent with high-dose liproxstatin-1 protecting via a lysosomal mechanism, we further de-monstrated that loss of viability induced by α-synuclein PFFs was attenuated by chloroquine and bafilomycin A1 as well as the lysosomal cysteine protease inhibitors, leupeptin, E-64D, and Ca-074-Me, but not other autophagy or lysosomal enzyme inhibitors. We confirmed using immunofluorescence microscopy that heparin prevented uptake of α-synuclein PFFs into cells but that chloroquine did not stop α-synuclein uptake into lysosomes despite impairing lysosomal function and inhibiting α-synuclein toxicity. Together, these data suggested that α-synuclein PFFs are toxic in functional lysosomes in vitro. Therapeutic strategies that prevent α-synuclein fibril uptake into lysosomes may be of benefit in PD.
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