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Single-nucleus multiomic atlas of ALS primary motor cortex nominates neuroprotective WDR49-expressing astrocytes

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Paper

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The authors' code

License · 21 lines · 1 KB · MIT

  1. MIT License
  3. Copyright (c) 2026 zhoujt1994
  5. Permission is hereby granted, free of charge, to any person obtaining a copy
  6. of this software and associated documentation files (the "Software"), to deal
  7. in the Software without restriction, including without limitation the rights
  8. to use, copy, modify, merge, publish, distribute, sublicense, and/or sell
  9. copies of the Software, and to permit persons to whom the Software is
  10. furnished to do so, subject to the following conditions:
  12. The above copyright notice and this permission notice shall be included in all
  13. copies or substantial portions of the Software.
  15. THE SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR
  16. IMPLIED, INCLUDING BUT NOT LIMITED TO THE WARRANTIES OF MERCHANTABILITY,
  17. FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT. IN NO EVENT SHALL THE
  18. AUTHORS OR COPYRIGHT HOLDERS BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER
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  20. OUT OF OR IN CONNECTION WITH THE SOFTWARE OR THE USE OR OTHER DEALINGS IN THE
  21. SOFTWARE.

LICENSE at commit 4802c56, under MIT · at the source

Overview

Authors: Sam Bonsall1, Rodrigo Siqueira Kazu1, Marianne King1, Diana Leung2, Farah Y Mahiddine1, J Robin Highley1, Andrew Strange1, Yongzhuo Chen3, Matilde Sassani1, Sara Cabras1,4, Katie M Bowden1, Hollie E Wareing1, Mahmoud K Eldahshoury4, James R Boyne4, Mark Collins5, Emma Marie Monte6, Calum Harvey1, Sarah B Gornall1, Akanksha Jangid1, Connie Treanor1
and 12 other authorsTobias Moll1,7, Charlotte H van Dijk8, Yiliang Huang6, Alex E Urban6, Pamela J Shaw1,7, Ryan J H West1, Kevin P Kenna8, Eran Hornstein9, Sai Zhang10, Johnathan Cooper-Knock1,7, Jingtian Zhou2, Michael P Snyder6,11
ORCID iDs: Sam Bonsall, Farah Y Mahiddine, Mahmoud K Eldahshoury, Mark Collins, Tobias Moll, Alex E Urban, Pamela J Shaw, Kevin P Kenna, Eran Hornstein, Sai Zhang, Johnathan Cooper-Knock, Jingtian Zhou, Michael P Snyder
  1. Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK
  2. Arc Institute, Palo Alto, CA, USA
  3. Department of Biostatistics, University of Florida, Gainesville, FL, USA
  4. Rita Levi Montalcini’ Department of Neuroscience, University of Turin, Turin, Italy Centre for Biomedical Science Research, School of Health, Leeds Beckett University, Leeds, UK
  5. School of Biosciences, University of Sheffield, Sheffield, UK
  6. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
  7. NIHR Sheffield Biomedical Research Centre, Sheffield, UK
  8. Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands
  9. Departments of Molecular Genetics and Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
  10. Department of Biomedical Informatics & Data Science, Yale University School of Medicine, New Haven, CT, USA
  11. Department of Genetics, Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA
Institutions: University of Sheffield (United Kingdom); Arc Research Institute; ARC Institute (Indonesia); University of Florida (United States); University of Turin (Italy); Leeds Beckett University (United Kingdom); Stanford University (United States); NIHR Sheffield Biomedical Research Centre (United Kingdom); University Medical Center Utrecht (Netherlands); Weizmann Institute of Science (Israel); Yale University (United States)
Journal: Research Square (preprint)
Dates: published online 1 June 2026
Type: Preprint · Language: English
License: CC BY
Identifiers: DOI 10.21203/rs.3.rs-9853460/v1 · OpenAlex W7162942433
Open access: green, a free copy (OpenAlex)
Status: empty repository
Categories: genetics / omics (modality), other condition (population)
Methods: Statistics, Smoothing, state filtering, decompositions, Machine learning, Preprocessing, Connectivity, fMRI & imaging
Topic: Amyotrophic Lateral Sclerosis Research (Neurology, Medicine), according to OpenAlex
Funding: National Institute for Health Research (NIHR) (NF-SI-0617-10077)
Citations: not cited yet (Europe PMC); 67 references in the paper

Abstract

Amyotrophic lateral sclerosis (ALS) causes selective neurodegeneration in primary motor cortex, yet cell-type-specific molecular changes driving this vulnerability remain poorly understood. We present an integrated single-nucleus RNA- and ATAC-sequencing atlas of 778,330 nuclei from the primary motor cortex of 140 genetically characterised donors. ALS is associated with widespread transcriptional reprogramming driven by a common set of transcription factors (TFs) across multiple cell-types. Astrocytes harbour the most differentially expressed genes. Within astrocytes, a WDR49-expressing subpopulation is spatially associated with TDP-43 pathology, and genetic variants within WDR49 confer risk for both sporadic and monogenic autosomal dominant ALS. In patient-derived induced astrocytes, WDR49 protein abundance predicts the survival of co-cultured neurons. WDR49 localises to PML nuclear bodies, where it regulates astrocyte reactivity and secretion of EVs containing protein chaperones. Together, these in vivo and in vitro findings suggest that WDR49+ astrocytes mount a compensatory secretory response to extracellular protein aggregates, and that loss of this capacity lowers the threshold for ALS pathogenesis.

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

Repository

Its files are read in the Code ↔ Paper reader above.

zhoujt1994/ALS_Multiome

License: MIT
State: the link answers, verified on 27 September 2026
Evidence: files inventoried
Commit: 4802c5635f32ebfb60f263923b6873b1a42db94d, 19 May 2026
Size: 2 files, 0 scripts
Software Heritage: not archived
Found in: “Data availability”
Holds: README, license file
Not found: CITATION.cff, environment file, tests, continuous integration, documentation
Availability: 1 check, the latest on 27 September 2026: the link answers
  • 27 September 2026: the link answers
2 files
At the source: github.com/zhoujt1994/ALS_Multiome.git

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

Tracing map

Proposed by the machine: these links were found in the paper and verified at the source, without human review. The map will receive a Zenodo DOI once one of the paper's authors has validated it with their ORCID.

What the map holds:

  • 1 repository of the authors' code, each at its verified commit, with its license and how the link was found in the paper;
  • 0 scripts, each with its path and the digest of its content;
  • no match between paragraphs and code yet;
  • neither the text of the paper nor the code itself.

Its JSON (tracing-map.json) is deposited on Zenodo with its DOI once the map is validated.

Data

No dataset and no data link were found in the paper.

Data availability

All raw RNA-seq data can be accessed via the National Center for Biotechnology Information’s Gene Expression Omnibus database (Bioproject ID is PRJNA1468995). In addition, we provide an interactive R Shiny app to visualize the gene expression and other clinical variable associations (https://sbonsall.shinyapps.io/ALS_Genetics_Browser/). Code is deposited at github repository: https://github.com/zhoujt1994/ALS_Multiome.git

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 2, 28 September 2026

  • Language: n/a → en

Version 1, 27 September 2026: the first record

Recorded: type, journal, dates, 32 authors, 1 funder, 65 references.

Cite

This paper

Bonsall, S., Kazu, R. S., King, M., Leung, D., Mahiddine, F. Y., Highley, J. R., Strange, A., Chen, Y., Sassani, M., Cabras, S., Bowden, K. M., Wareing, H. E., Eldahshoury, M. K., Boyne, J. R., Collins, M., Monte, E. M., Harvey, C., Gornall, S. B., Jangid, A., . . . Snyder, M. P. (2026). Single-nucleus multiomic atlas of ALS primary motor cortex nominates neuroprotective WDR49-expressing astrocytes. Research Square (preprint). https://doi.org/10.21203/rs.3.rs-9853460/v1

BibTeX

@article{bonsall2026single,
author = {Bonsall, Sam and Kazu, Rodrigo Siqueira and King, Marianne and Leung, Diana and Mahiddine, Farah Y and Highley, J Robin and Strange, Andrew and Chen, Yongzhuo and Sassani, Matilde and Cabras, Sara and Bowden, Katie M and Wareing, Hollie E and Eldahshoury, Mahmoud K and Boyne, James R and Collins, Mark and Monte, Emma Marie and Harvey, Calum and Gornall, Sarah B and Jangid, Akanksha and Treanor, Connie and Moll, Tobias and van Dijk, Charlotte H and Huang, Yiliang and Urban, Alex E and Shaw, Pamela J and West, Ryan J H and Kenna, Kevin P and Hornstein, Eran and Zhang, Sai and Cooper-Knock, Johnathan and Zhou, Jingtian and Snyder, Michael P},
title = {{Single-nucleus multiomic atlas of ALS primary motor cortex nominates neuroprotective WDR49-expressing astrocytes}},
journal = {Research Square (preprint)},
year = {2026},
month = jun,
publisher = {Research Square},
issn = {2693-5015},
doi = {10.21203/rs.3.rs-9853460/v1},
url = {https://doi.org/10.21203/rs.3.rs-9853460/v1}
}

RIS

TY - JOUR
AU - Bonsall, Sam
AU - Kazu, Rodrigo Siqueira
AU - King, Marianne
AU - Leung, Diana
AU - Mahiddine, Farah Y
AU - Highley, J Robin
AU - Strange, Andrew
AU - Chen, Yongzhuo
AU - Sassani, Matilde
AU - Cabras, Sara
AU - Bowden, Katie M
AU - Wareing, Hollie E
AU - Eldahshoury, Mahmoud K
AU - Boyne, James R
AU - Collins, Mark
AU - Monte, Emma Marie
AU - Harvey, Calum
AU - Gornall, Sarah B
AU - Jangid, Akanksha
AU - Treanor, Connie
AU - Moll, Tobias
AU - van Dijk, Charlotte H
AU - Huang, Yiliang
AU - Urban, Alex E
AU - Shaw, Pamela J
AU - West, Ryan J H
AU - Kenna, Kevin P
AU - Hornstein, Eran
AU - Zhang, Sai
AU - Cooper-Knock, Johnathan
AU - Zhou, Jingtian
AU - Snyder, Michael P
TI - Single-nucleus multiomic atlas of ALS primary motor cortex nominates neuroprotective WDR49-expressing astrocytes
T2 - Research Square (preprint)
J2 - Res Sq
PY - 2026
DA - 2026/06/01
SN - 2693-5015
PB - Research Square
DO - 10.21203/rs.3.rs-9853460/v1
UR - https://doi.org/10.21203/rs.3.rs-9853460/v1
LA - en
ER -

CSL-JSON

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