{"id":"doi:10.1038/s41467-026-76173-4","kind":"article","title":"α-Synuclein blocks endoplasmic reticulum co-translational protein translocation early in Parkinson's disease","authors":["Lam CL","Gatford NJF","Aragón-González A","Tanudjojo B","Sahoo A","Castle AR","Agarwal D","Jainarayanan A","Hester SS","Sen N","Benesch JLP","Fischer R","Sims D","Tofaris GK"],"author_count":14,"year":2026,"published":"2026-08-06","venue":"Nature communications","cited_by":0,"doi":"10.1038/s41467-026-76173-4","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41467-026-76173-4","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41467-026-76173-4","updated":null,"pmid":"42562827","pmcid":"PMC13448182","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC13448182/pdf","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.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"α-Synuclein blocks endoplasmic reticulum co-translational protein translocation early in Parkinson's disease\" by Lam CL, Gatford NJF, Aragón-González A et al., https://doi.org/10.1038/s41467-026-76173-4, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"gene-cell-therapy","name":"Gene & Cell Therapy","domain_slug":"medicine"}],"cited_in_dossiers":[]}