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α-Synuclein blocks endoplasmic reticulum co-translational protein translocation early in Parkinson's disease.

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Τίτλος: α-Synuclein blocks endoplasmic reticulum co-translational protein translocation early in Parkinson's disease.
Συγγραφείς: Lam CL; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK., Gatford NJF; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK., Aragón-González A; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK., Tanudjojo B; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK., Sahoo A; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK., Castle AR; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK., Agarwal D; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Jainarayanan A; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK., Hester SS; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Sen N; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.; Department of Chemistry, University of Oxford, Oxford, UK., Benesch JLP; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.; Department of Chemistry, University of Oxford, Oxford, UK., Fischer R; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Sims D; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Tofaris GK; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. george.tofaris@ndcn.ox.ac.uk.; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK. george.tofaris@ndcn.ox.ac.uk.
Πηγή: Nature communications [Nat Commun] 2026 Aug 06; Vol. 17 (1). Date of Electronic Publication: 2026 Aug 06.
Τύπος έκδοσης: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Imprint Name(s): Original Publication: [London] : Nature Pub. Group
Ιατρικοί όροι (MeSH): alpha-Synuclein*/metabolism , alpha-Synuclein*/genetics , Parkinson Disease*/metabolism , Parkinson Disease*/pathology , Parkinson Disease*/genetics , Endoplasmic Reticulum*/metabolism, Dopaminergic Neurons/metabolism ; Induced Pluripotent Stem Cells/metabolism ; SEC Translocation Channels/metabolism ; Lysosomes/metabolism ; Brain/metabolism ; Brain/pathology ; Proteasome Endopeptidase Complex/metabolism ; Humans ; Protein Transport
Περίληψη: The primary mechanism and subcellular localisation of α-synuclein toxicity in Parkinson's disease pathogenesis remain unknown. We spatially and temporally resolved proteomic and transcriptomic changes in human iPSC-derived dopaminergic neurons with increasing burden of pathological α-synuclein. We found that misfolded α-synuclein proteoforms, signified by the formation of nanoscale intraneuronal puncta, are associated with impaired translocon function at the endoplasmic reticulum (ER). We show that α-synuclein interacts with Sec61A in iPSC-derived dopaminergic neurons and in post-mortem brain tissue from patients with Parkinson's disease. This interaction interferes with the co-translational translocation of ER-processed proteins including the vacuolar-type ATPase V0a1 subunit, glucocerebrosidase, and Cathepsin B, causing defective organelle function such as reduced lysosomal acidification, leading to increased extracellular vesicle release of α-synuclein. Defective ER-translocation was associated with increased ribosomal UFMylation and proteasomal recruitment but not activation of the unfolded protein response. Reduction of pathological α-synuclein by either CRISPRi to decrease α-synuclein expression or pharmacological activation of proteasomal degradation with repurposed drugs mitigates the ER defect. Our study offers a unifying mechanistic link between α-synuclein pathology and dysregulation of diverse organelle-associated proteins that are both Sec61A translocon substrates and genetic modifiers of Parkinson's disease risk. Our data also provide a therapeutic rationale for proteasomal activation in early Parkinson's disease.
(© 2026. The Author(s).)
Competing Interests: Competing interests: The authors declare no competing interests.
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Grant Information: United Kingdom WT_ Wellcome Trust; R01 GM129325 United States GM NIGMS NIH HHS; MR/V007068/1 United Kingdom MRC_ Medical Research Council
Substance Nomenclature: 0 (alpha-Synuclein)
0 (SEC Translocation Channels)
EC 3.4.25.1 (Proteasome Endopeptidase Complex)
Entry Date(s): Date Created: 20260806 Date Completed: 20260806 Latest Revision: 20260826
Update Code: 20260826
PubMed Central ID: PMC13448182
DOI: 10.1038/s41467-026-76173-4
PMID: 42562827
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2041-1723
DOI:10.1038/s41467-026-76173-4