OSCR

Large-scale bidirectional arrayed genetic screens identify OXR1 and EMC4 as modifiers of αSynuclein aggregation.

Overview

Authors: Sandesh Neupane1,2, Lea Nikolić3, Lorenzo Maraio1,2, Thomas Goiran4, Nathan Karpilovsky4, Stefano Sellitto5, Vangelis Bouris1,2, Jiang‐An Yin6, Ronald Melki7, Edward A Fon4, Adriano Aguzzi1, Elena De Cecco1,2
ORCID iDs: Lea Nikolić, Stefano Sellitto, Ronald Melki, Elena De Cecco
  1. Institute for the Science of the Aging Brain, St. Gallen, Switzerland
  2. Institute of Neuropathology, University of Zurich, Switzerland
  3. Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy
  4. Neurodegenerative Diseases Research Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute‐Hospital, McGill University, Canada
  5. Department of Biology, University of Padova, Italy
  6. Aging and Regeneration Center, School of Basic Medical Sciences, Tsinghua University, Beijing, P. R. China
  7. Institut François Jacob (MIRCen) and CNRS, Fontenay‐aux‐Roses, France
Institutions: University of Zurich (Switzerland); ISAB - Institute for the Science of the Aging Brain (Switzerland); Scuola Internazionale Superiore di Studi Avanzati (Italy); Montreal Neurological Institute and Hospital (Canada); McGill University (Canada); University of Padua (Italy); Tsinghua University (China); Centre National de la Recherche Scientifique (France); Molecular Imaging Research Center (France)
Journal: FEBS open bio, volume 16, issue 8, pages 1563-1592
Dates: received 19 February 2026; accepted 10 March 2026; published online 30 March 2026; in print August 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1002/2211-5463.70233 · PMID 41911287 · PMCID PMC13398675 · OpenAlex W7143457521
Open access: gold, a free copy (OpenAlex)
Status: code on request (how the code is found and verified)
Categories: human (organism), Parkinson's (population), cellular / molecular (subfield)
Methods: Spectral & time-frequency, Statistics, Machine learning, Evoked potentials, Connectivity, fMRI & imaging
Keywords: autophagy‐lysosomal pathway, CRISPR screening, mitochondrial dysfunction, neurodegeneration, synucleinopathies, αSynuclein aggregation
MeSH: alpha-Synuclein*, Mitochondrial Proteins*, Endoplasmic Reticulum, HEK293 Cells, Humans, Mitochondria, Parkinson Disease, Protein Aggregates, Protein Aggregation, Pathological (* major topic)
Topic: Parkinson's Disease Mechanisms and Treatments (Clinical Neurology, Medicine), according to OpenAlex
Funding: Swiss National Science Foundation (227951, 179040, 207872)
Citations: not cited yet (Europe PMC); 101 references in the paper

Abstract

In Parkinson's disease and other synucleinopathies, αSynuclein (αSyn) misfolds and forms Ser129‐phosphorylated aggregates (pSyn129) with the factors controlling this process largely unknown. Here, we used arrayed CRISPR‐mediated gene activation and ablation to discover new pSyn129 modulators. Using quadruple‐guide RNAs (qgRNAs) and Cas9, or an inactive Cas9 fused to a synthetic transactivator, we ablated 2304 and activated 2428 human genes related to mitochondria, trafficking, and motility functions in HEK293 cells. After exposure of cells to αSyn fibrils, pSyn129 signals were recorded by high‐throughput fluorescence microscopy and aggregates were identified by image analysis. We found that pSyn129 was increased by activating the mitochondrial protein OXR1, which decreased ATP levels and altered the mitochondrial membrane potential. Instead, pSyn129 was reduced by ablation of the endoplasmic reticulum (ER)‐associated protein EMC4, which enhanced ER‐driven autophagic flux and lysosomal clearance. OXR1 activation preferentially modulated cellular reactions to fibrils derived from multiple system atrophy (MSA) patients, whereas EMC4 ablation broadly reduced pSyn129 across diverse αSyn polymorphs. These findings were confirmed in human iPSC‐derived cortical and dopaminergic neurons, where OXR1 preferentially promoted somatic aggregation and EMC4 reduced both somatic and neuritic aggregates. These results uncover previously unrecognized roles for OXR1 and EMC4 in αSyn aggregation, thereby broadening our mechanistic understanding of synucleinopathies.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none (its code is available on request), so it has no map.

Data

Datasets cited

Data accessibility

All data supporting the findings of this study are included in this published article and its Supporting Information files. Raw microscopy images generated during this study have been deposited in FigShare (https://figshare.com/s/ce7273dfd93096f9c01e; will be made public upon publication) and Zenodo (DOI: 10.5281/zenodo.15358052 (https://doi.org/10.5281/zenodo.15358052)). Bulk RNA sequencing data will be available through the Gene Expression Omnibus (GEO) under accession number GSE295558 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE295558) upon publication, in accordance with NIH data sharing policies. Source data are provided with this paper.

This study did not generate novel computational code. Data analysis and visualization (e.g., statistical tests, violin plots, volcano plots) were performed using standard functions in R (version 4.3.1) with publicly available packages (e.g., ggplot2, dplyr). The CellProfiler pipeline used to analyze pSyn129 staining in HEK cells, neurites, and soma is available from the corresponding author upon reasonable request.

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, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 6 keywords, 9 MeSH terms, 1 funder, 98 references.

Cite

This paper

Neupane, S., Nikolić, L., Maraio, L., Goiran, T., Karpilovsky, N., Sellitto, S., Bouris, V., Yin, J., Melki, R., Fon, E. A., Aguzzi, A., & De Cecco, E. (2026). Large-scale bidirectional arrayed genetic screens identify OXR1 and EMC4 as modifiers of αSynuclein aggregation. FEBS open bio, 16(8), 1563-1592. https://doi.org/10.1002/2211-5463.70233

BibTeX

@article{neupane2026large,
author = {Neupane, Sandesh and Nikolić, Lea and Maraio, Lorenzo and Goiran, Thomas and Karpilovsky, Nathan and Sellitto, Stefano and Bouris, Vangelis and Yin, Jiang‐An and Melki, Ronald and Fon, Edward A and Aguzzi, Adriano and De Cecco, Elena},
title = {{Large-scale bidirectional arrayed genetic screens identify OXR1 and EMC4 as modifiers of αSynuclein aggregation}},
journal = {FEBS open bio},
year = {2026},
month = mar,
volume = {16},
number = {8},
pages = {1563--1592},
publisher = {Wiley},
issn = {2211-5463},
doi = {10.1002/2211-5463.70233},
url = {https://doi.org/10.1002/2211-5463.70233},
pmid = {41911287},
pmcid = {PMC13398675}
}

RIS

TY - JOUR
AU - Neupane, Sandesh
AU - Nikolić, Lea
AU - Maraio, Lorenzo
AU - Goiran, Thomas
AU - Karpilovsky, Nathan
AU - Sellitto, Stefano
AU - Bouris, Vangelis
AU - Yin, Jiang‐An
AU - Melki, Ronald
AU - Fon, Edward A
AU - Aguzzi, Adriano
AU - De Cecco, Elena
TI - Large-scale bidirectional arrayed genetic screens identify OXR1 and EMC4 as modifiers of αSynuclein aggregation
T2 - FEBS open bio
J2 - FEBS Open Bio
PY - 2026
DA - 2026/03/30
VL - 16
IS - 8
SP - 1563
EP - 1592
SN - 2211-5463
PB - Wiley
DO - 10.1002/2211-5463.70233
UR - https://doi.org/10.1002/2211-5463.70233
LA - en
ER -

CSL-JSON

{
"id": "10.1002/2211-5463.70233",
"type": "article-journal",
"title": "Large-scale bidirectional arrayed genetic screens identify OXR1 and EMC4 as modifiers of αSynuclein aggregation",
"container-title": "FEBS open bio",
"author": [
{
"family": "Neupane",
"given": "Sandesh"
},
{
"family": "Nikolić",
"given": "Lea"
},
{
"family": "Maraio",
"given": "Lorenzo"
},
{
"family": "Goiran",
"given": "Thomas"
},
{
"family": "Karpilovsky",
"given": "Nathan"
},
{
"family": "Sellitto",
"given": "Stefano"
},
{
"family": "Bouris",
"given": "Vangelis"
},
{
"family": "Yin",
"given": "Jiang‐An"
},
{
"family": "Melki",
"given": "Ronald"
},
{
"family": "Fon",
"given": "Edward A"
},
{
"family": "Aguzzi",
"given": "Adriano"
},
{
"family": "De Cecco",
"given": "Elena"
}
],
"container-title-short": "FEBS Open Bio",
"volume": "16",
"issue": "8",
"page": "1563-1592",
"DOI": "10.1002/2211-5463.70233",
"PMID": "41911287",
"PMCID": "PMC13398675",
"ISSN": "2211-5463",
"publisher": "Wiley",
"URL": "https://doi.org/10.1002/2211-5463.70233",
"language": "en",
"issued": {
"date-parts": [
[
2026,
3,
30
]
]
}
}

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1101/2025.06.10.658866
Large-scale bidirectional arrayed genetic screens identify <i>OXR1</i> and <i>EMC4</i> as modifiers of α-synuclein aggregation
Journal: bioRxiv (preprint)
In common: Zenodo 15358052, Parkinson's, cellular / molecular, 69 references, 3 authors
[2] doi:10.1016/j.nbd.2026.107379 [code]
DYRK1A and Parkinson's disease, facts and hypotheses.
Journal: Neurobiology of disease
In common: Parkinson's, cellular / molecular, 9 references
[3] doi:10.1186/s40478-024-01785-0
Alpha-synuclein aggregates are phosphatase resistant.
Journal: Acta neuropathologica communications
In common: Parkinson's, cellular / molecular, 5 references, author Ronald Melki
[4] doi:10.1186/s40035-026-00535-7
Mapping cellular vulnerability in Parkinson's disease using retro-AAVs and preformed α-synuclein fibrils.
Journal: Translational neurodegeneration
In common: Parkinson's, cellular / molecular, 9 references
[5] doi:10.1126/sciadv.adq3539
Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases.
Journal: Science advances
In common: Parkinson's, cellular / molecular, 8 references
[6] doi:10.1038/s41531-024-00679-1
Neither alpha-synuclein fibril strain nor host murine genotype influences seeding efficacy.
Journal: NPJ Parkinson's disease
In common: Parkinson's, 3 references, author Ronald Melki
[7] doi:10.1038/s41467-025-66146-4
Seed amplification of MSA alpha-synuclein aggregates preserves the biological and structural properties of brain-derived aggregates.
Journal: Nature communications
In common: Parkinson's, cellular / molecular, 6 references
[8] doi:10.1038/s42003-023-04884-1
α-Synuclein fibril and synaptic vesicle interactions lead to vesicle destruction and increased lipid-associated fibril uptake into iPSC-derived neurons.
Journal: Communications biology
In common: Parkinson's, cellular / molecular, 6 references
[9] doi:10.1038/s41551-025-01496-4 [code]
Large-scale visualization of α-synuclein oligomers in Parkinson's disease brain tissue.
Journal: Nature biomedical engineering
In common: Parkinson's, cellular / molecular, 6 references
[10] doi:10.1038/s41467-026-73003-5 [code]
Gpnmb defines a phagocytic state of microglia linked to cell death in prion disease mouse model.
Journal: Nature communications
In common: cellular / molecular, 2 references, author Elena De Cecco

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Sign in with ORCID to claim this paper as one of its authors, correct its record or validate its tracing map: when the paper's metadata lists your ORCID iD, you are recognized at once. Maintainers of its code: sign in with GitHub, then claim the repository on your account page.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion, reproductions, activity

Discussion: code errors and mismatches between the code and the paper about this paper and its code, from readers and its authors, beside the paper and its tracing map.

Reproductions: reports from readers who ran the authors' code and did not get the paper's result, what they ran, with which environment, commit and data.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.