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

Article · 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

- Archive id: doi:10.1038/s41467-026-76173-4
- Published: 2026-08-06
- Venue: Nature communications
- DOI: https://doi.org/10.1038/s41467-026-76173-4
- PMID: 42562827
- PMCID: PMC13448182
- Citations: 0
- Source URL: https://doi.org/10.1038/s41467-026-76173-4
- PDF: https://europepmc.org/articles/PMC13448182/pdf
- Provenance: europepmc

## 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 reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Gene & Cell Therapy](https://space-kitty.com/topics/gene-cell-therapy)

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