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

Authors

Chor Lai Lam, Nicholas J F Gatford, Ana Aragón-González, Benedict Tanudjojo, Anis Sahoo, Andrew R Castle, Devika Agarwal, Ashwin Jainarayanan, Svenja S Hester, Navoneel Sen, Justin L P Benesch, Roman Fischer, David Sims, George K Tofaris

Published in

Nature communications. Volume 17. Issue 1. Aug 06, 2026. Epub Aug 06, 2026.

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.

PMID:
42562827
Bibliographic data and abstract were imported from PubMed on 07 Aug 2026.

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