OSCR

UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration.

Overview

Authors: Yang Liu1,2, Zhiyuan Huang1,2, Yu-Wen Hsu1,2, Pragney Deme3, Ashley M Frankenfield4, Suheng Wu1,2, Xiaofeng Zhao1,2, Honghe Liu1,2, Tao Zhang1,2, Elizabeth J Alexander1,2, Mingming Liu1,2, Yanjun Zhang1,2, Haocheng Wang1,2, Yixin Zhou1,2, Mervyn J Monteiro5, Ling Hao4,6, Norman J Haughey3, Jiou Wang1,2
ORCID iDs: Yang Liu, Yu-Wen Hsu, Pragney Deme, Mingming Liu, Yanjun Zhang, Mervyn J Monteiro, Ling Hao, Norman J Haughey, Jiou Wang
  1. Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD USA
  2. Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD USA
  3. Department of Physiology, School of Medicine, Tulane University, New Orleans, LA USA
  4. Department of Chemistry, George Washington University, Washington, DC USA
  5. Department of Neurobiology, University of Maryland, Baltimore, MD USA
  6. Department of Chemistry & Biochemistry, University of Maryland, College Park, MD USA
Institutions: Johns Hopkins University (United States); Tulane University (United States); George Washington University (United States); University of Maryland, Baltimore (United States); University of Maryland, College Park (United States)
Journal: Nature neuroscience, volume 29, issue 4, pages 782-795
Dates: received 7 August 2024; accepted 26 January 2026; published online 30 March 2026; in print 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41593-026-02226-y · PMID 41912662 · PMCID PMC13058728 · OpenAlex W7143322012
Open access: hybrid, a free copy (OpenAlex)
Status: data only (how the code is found and verified)
Categories: human (organism), mouse (organism), other condition (population), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Spectral & time-frequency, Statistics, Machine learning
Keywords: Lipids, Amyotrophic lateral sclerosis, Mechanisms of disease
MeSH: Adaptor Proteins, Signal Transducing*, Autophagy-Related Proteins*, Cell Cycle Proteins*, Lipid Metabolism*, Neurodegenerative Diseases*, Amyotrophic Lateral Sclerosis, Animals, Frontotemporal Dementia, Humans, Induced Pluripotent Stem Cells, Mice, Mutation, Neurons, Proteotoxic Stress (* major topic)
Topic: Amyotrophic Lateral Sclerosis Research (Clinical Neurology, Medicine), according to OpenAlex
Funding: U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) (NS089616, NS098243, NS128494, NS074324, NS110098); Target ALS (Target ALS Foundation) (FS-2023-SBF-S6); NINDS NIH HHS (R01 NS074324, R01 NS110098, R01 NS098243, R01 NS128494, R01 NS089616, RF1 NS098243, RF1 NS074324)
Citations: cited by 3 papers (Europe PMC); 78 references in the paper
Research resources: RRID:Addgene_107502, a gift from Alejandro Gutierrez RRID:Addgene_107507

Abstract

Protein homeostasis and lipid metabolism are essential processes frequently disrupted in neurodegenerative diseases. However, their mechanistic intersection in disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unclear. Ubiquilin 2 (UBQLN2) is a protein quality control factor linked to ALS/FTD. Through multi-omic analyses of induced pluripotent stem cell (iPSC)-derived neurons harboring disease-associated UBQLN2 mutations, we uncovered UBQLN2 as a molecular hub linking lipid dysregulation and proteostasis, the perturbation of which contributes to neurodegeneration. UBQLN2 mediated the degradation of ILVBL (acetolactate synthase-like protein) and ALDH3A2 (aldehyde dehydrogenase 3 family member A2), two enzymes essential for mitochondrial lipid catabolism associated with lipid droplets and neuronal viability. ALS/FTD-linked UBQLN2 mutations and TAR DNA-binding protein 43 (TDP-43) pathology impair the degradation of ILVBL and ALDH3A2, leading to metabolic dysfunction and neurodegeneration. Restoring the UBQLN2–ILVBL/ALDH3A2 axis attenuates neurodegenerative phenotypes in neurons, organoids and mice, establishing UBQLN2 as a critical regulator of metabolic homeostasis in ALS/FTD and other related neurodegenerative diseases.

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

Code

The paper links to its data and to no code of its authors: see the Data section.

Code availability

No custom software codes were used to analyze the data.

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

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

Data availability

The omics data generated in this study are included in the supplementary materials (Supplementary Tables 1–6). LC–MS/MS data are deposited in the ProteomeXchange with a unique identifier: PXD048152 (http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD048152). The raw RNA-seq data are deposited to the Gene Expression Omnibus database (GSE272994 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE272994)). Source data are provided with this paper.

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, 18 authors, 3 keywords, 14 MeSH terms, 3 funders, 74 references, 2 RRIDs.

Cite

This paper

Liu, Y., Huang, Z., Hsu, Y.-W., Deme, P., Frankenfield, A. M., Wu, S., Zhao, X., Liu, H., Zhang, T., Alexander, E. J., Liu, M., Zhang, Y., Wang, H., Zhou, Y., Monteiro, M. J., Hao, L., Haughey, N. J., & Wang, J. (2026). UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration. Nature neuroscience, 29(4), 782-795. https://doi.org/10.1038/s41593-026-02226-y

BibTeX

@article{liu2026ubqln2,
author = {Liu, Yang and Huang, Zhiyuan and Hsu, Yu-Wen and Deme, Pragney and Frankenfield, Ashley M and Wu, Suheng and Zhao, Xiaofeng and Liu, Honghe and Zhang, Tao and Alexander, Elizabeth J and Liu, Mingming and Zhang, Yanjun and Wang, Haocheng and Zhou, Yixin and Monteiro, Mervyn J and Hao, Ling and Haughey, Norman J and Wang, Jiou},
title = {{UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration}},
journal = {Nature neuroscience},
year = {2026},
month = mar,
volume = {29},
number = {4},
pages = {782--795},
publisher = {Nature Portfolio},
issn = {1097-6256},
doi = {10.1038/s41593-026-02226-y},
url = {https://doi.org/10.1038/s41593-026-02226-y},
pmid = {41912662},
pmcid = {PMC13058728}
}

RIS

TY - JOUR
AU - Liu, Yang
AU - Huang, Zhiyuan
AU - Hsu, Yu-Wen
AU - Deme, Pragney
AU - Frankenfield, Ashley M
AU - Wu, Suheng
AU - Zhao, Xiaofeng
AU - Liu, Honghe
AU - Zhang, Tao
AU - Alexander, Elizabeth J
AU - Liu, Mingming
AU - Zhang, Yanjun
AU - Wang, Haocheng
AU - Zhou, Yixin
AU - Monteiro, Mervyn J
AU - Hao, Ling
AU - Haughey, Norman J
AU - Wang, Jiou
TI - UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration
T2 - Nature neuroscience
J2 - Nat Neurosci
PY - 2026
DA - 2026/03/30
VL - 29
IS - 4
SP - 782
EP - 795
SN - 1097-6256
PB - Nature Portfolio
DO - 10.1038/s41593-026-02226-y
UR - https://doi.org/10.1038/s41593-026-02226-y
LA - en
ER -

CSL-JSON

{
"id": "10.1038/s41593-026-02226-y",
"type": "article-journal",
"title": "UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration",
"container-title": "Nature neuroscience",
"author": [
{
"family": "Liu",
"given": "Yang"
},
{
"family": "Huang",
"given": "Zhiyuan"
},
{
"family": "Hsu",
"given": "Yu-Wen"
},
{
"family": "Deme",
"given": "Pragney"
},
{
"family": "Frankenfield",
"given": "Ashley M"
},
{
"family": "Wu",
"given": "Suheng"
},
{
"family": "Zhao",
"given": "Xiaofeng"
},
{
"family": "Liu",
"given": "Honghe"
},
{
"family": "Zhang",
"given": "Tao"
},
{
"family": "Alexander",
"given": "Elizabeth J"
},
{
"family": "Liu",
"given": "Mingming"
},
{
"family": "Zhang",
"given": "Yanjun"
},
{
"family": "Wang",
"given": "Haocheng"
},
{
"family": "Zhou",
"given": "Yixin"
},
{
"family": "Monteiro",
"given": "Mervyn J"
},
{
"family": "Hao",
"given": "Ling"
},
{
"family": "Haughey",
"given": "Norman J"
},
{
"family": "Wang",
"given": "Jiou"
}
],
"container-title-short": "Nat Neurosci",
"volume": "29",
"issue": "4",
"page": "782-795",
"DOI": "10.1038/s41593-026-02226-y",
"PMID": "41912662",
"PMCID": "PMC13058728",
"ISSN": "1097-6256",
"publisher": "Nature Portfolio",
"URL": "https://doi.org/10.1038/s41593-026-02226-y",
"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:10.1016/j.isci.2024.111642 [code]
Insulin acts on astrocytes to shift their substrate preference to fatty acids.
Journal: iScience
In common: cellular / molecular, 2 authors
[2] doi:10.1038/s44318-025-00591-1
Ubiquilin-2 liquid droplets catalyze α-synuclein fibril formation.
Journal: The EMBO journal
In common: Alzheimer's / dementia, cellular / molecular, 6 references
[3] doi:10.7554/elife.104057 [code]
Maintenance of neuronal TDP-43 expression requires axonal lysosome transport.
Journal: eLife
In common: cellular / molecular, 3 references, author Ling Hao
[4] doi:10.1186/s13024-023-00673-w [code]
Multi-modal proteomic characterization of lysosomal function and proteostasis in progranulin-deficient neurons.
Journal: Molecular neurodegeneration
In common: Alzheimer's / dementia, mouse, cellular / molecular, 2 references, author Ling Hao
[5] doi:10.1038/s41467-025-59679-1 [code]
Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS.
Journal: Nature communications
In common: other condition, cellular / molecular, 6 references
[6] doi:10.7554/elife.79452 [code]
UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS.
Journal: eLife
In common: other condition, cellular / molecular, 5 references
[7] doi:10.1186/s13024-026-00944-2
TDP-43: [GU]-ardian of the transcriptome.
Journal: Molecular neurodegeneration
In common: other condition, cellular / molecular, 5 references
[8] doi:10.1039/d4an01573h [code]
Evaluating sample normalization methods for MS-based multi-omics and the application to a neurodegenerative mouse model.
Journal: The Analyst
In common: other condition, mouse, cellular / molecular, 1 reference, author Ling Hao
[9] doi:10.1016/j.celrep.2025.116841
Inducible deletion of DGAT1 and 2 from microglia exacerbates neurodegeneration and endolysosomal lipid accumulation in male PS19 mice.
Journal: Cell reports
In common: Alzheimer's / dementia, other condition, mouse, 1 other category, 4 references
[10] doi:10.1186/s40478-023-01656-0
Modelling TDP-43 proteinopathy in Drosophila uncovers shared and neuron-specific targets across ALS and FTD relevant circuits.
Journal: Acta neuropathologica communications
In common: Alzheimer's / dementia, other condition, 5 references

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.