α-Synuclein blocks endoplasmic reticulum co-translational protein translocation early in Parkinson's disease.
Overview
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
- Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Department of Chemistry, University of Oxford, Oxford, UK
Abstract
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.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
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Data
Datasets cited
- geo:GSE276377, at NCBI GEO; found in “Data availability”
Data availability
Supplementary Information is available for this paper. All data supporting the findings of this manuscript are available from the corresponding author upon request. Correspondence and requests for materials should be addressed to data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD055581. Bulk RNA-seq data are available at GEO under accession number GSE276377 (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 5 keywords, 11 MeSH terms, 3 funders, 60 references.
Cite
This paper
Lam, C. L., Gatford, N. J. F., Aragón-González, A., Tanudjojo, B., Sahoo, A., Castle, A. R., Agarwal, D., Jainarayanan, A., Hester, S. S., Sen, N., Benesch, J. L. P., Fischer, R., Sims, D., & Tofaris, G. K. (2026). α-Synuclein blocks endoplasmic reticulum co-translational protein translocation early in Parkinson's disease. Nature communications, 17(1), 7768. https://
BibTeX
@article{lam2026synuclei
author = {Lam, Chor Lai and Gatford, Nicholas J F and Aragón-González, Ana and Tanudjojo, Benedict and Sahoo, Anis and Castle, Andrew R and Agarwal, Devika and Jainarayanan, Ashwin and Hester, Svenja S and Sen, Navoneel and Benesch, Justin L P and Fischer, Roman and Sims, David and Tofaris, George K},
title = {{α-Synuclein blocks endoplasmic reticulum co-translational protein translocation early in Parkinson's disease}},
journal = {Nature communications},
year = {2026},
month = aug,
volume = {17},
number = {1},
pages = {7768},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/
url = {https://
pmid = {42562827},
pmcid = {PMC13448182}
}
RIS
TY - JOUR
AU - Lam, Chor Lai
AU - Gatford, Nicholas J F
AU - Aragón-González, Ana
AU - Tanudjojo, Benedict
AU - Sahoo, Anis
AU - Castle, Andrew R
AU - Agarwal, Devika
AU - Jainarayanan, Ashwin
AU - Hester, Svenja S
AU - Sen, Navoneel
AU - Benesch, Justin L P
AU - Fischer, Roman
AU - Sims, David
AU - Tofaris, George K
TI - α-Synuclein blocks endoplasmic reticulum co-translational protein translocation early in Parkinson's disease
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/
VL - 17
IS - 1
SP - 7768
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/
UR - https://
LA - en
ER -
CSL-JSON
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