Evidence map›Paper›PMID 41912662›Full record

ArticleNature neuroscience2026

UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration.

Yang Liu, Zhiyuan Huang, Yu-Wen Hsu, Pragney Deme, Ashley M Frankenfield, Suheng Wu, Xiaofeng Zhao, Honghe Liu, Tao Zhang, Elizabeth J Alexander and 8 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature neuroscience, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors.

Yang Liu *Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. yliu238@jh.edu.ORCID http://orcid.org/0000-0001-5892-7448
Zhiyuan Huang *Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Yu-Wen HsuDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-6126-8938
Pragney DemeDepartment of Physiology, School of Medicine, Tulane University, New Orleans, LA, USA.
Ashley M FrankenfieldDepartment of Chemistry, George Washington University, Washington, DC, USA.
Suheng WuDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Xiaofeng ZhaoDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Honghe LiuDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Tao ZhangDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Elizabeth J AlexanderDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Mingming LiuDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0003-2614-3678
Yanjun ZhangDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0009-0002-8531-6604
Haocheng WangDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Yixin ZhouDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Mervyn J MonteiroDepartment of Neurobiology, University of Maryland, Baltimore, MD, USA.
Ling HaoDepartment of Chemistry, George Washington University, Washington, DC, USA.
Norman J HaugheyDepartment of Physiology, School of Medicine, Tulane University, New Orleans, LA, USA.
Jiou WangDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. jiouw@jhmi.edu.ORCID http://orcid.org/0000-0003-0204-8932

Funding

Neurodegeneration and Proteotoxicity Dissected in C. elegans and MammalsR01NS074324 · NINDS · JOHNS HOPKINS UNIVERSITY · PI WANG, JIOU · 2011 to 2025
$6.2M
Investigating the role of C9orf72 in autophagic and metabolic dysregulation in ALS/FTDR01NS089616 · NINDS · JOHNS HOPKINS UNIVERSITY · PI Jiou Wang · 2015 to 2026
$6.0M
Mechanisms of RNA and Protein Dysregulations in ALS/FTD Associated with FUS and Ubiquilin 2R01NS110098 · NINDS · JOHNS HOPKINS UNIVERSITY · PI Jiou Wang · 2019 to 2026
$5.0M
Mechanistic studies and therapeutics for ALS/FTD linked to UBQLN2 mutationsR01NS098243 · NINDS · UNIVERSITY OF MARYLAND BALTIMORE · PI Mervyn J Monteiro · 2017 to 2026
$4.0M
Molecular Basis of Pathogenic Cascades in ALS/FTD Initiated from C9orf72 Hexanucleotide Repeat ExpansionR01NS128494 · NINDS · JOHNS HOPKINS UNIVERSITY · PI Jiou Wang · 2022 to 2026
$3.1M
Mechanistic studies and therapeutics for ALS/FTD linked to UBQLN2 mutationsRF1NS098243 · NINDS · UNIVERSITY OF MARYLAND BALTIMORE · PI MONTEIRO, MERVYN J · 2022 to 2022
$2.2M
Investigating Novel Mechanisms Regulating Proteotoxic Stress and Protein Quality Control in ALS/FTDRF1NS074324 · NINDS · JOHNS HOPKINS UNIVERSITY · PI Jiou Wang · 2026 to 2026
$945k
NINDS NIH HHS R01 NS074324NINDS NIH HHS R01 NS089616NINDS NIH HHS R01 NS098243NINDS NIH HHS R01 NS110098NINDS NIH HHS R01 NS128494NINDS NIH HHS RF1 NS074324NINDS NIH HHS RF1 NS098243Target ALS (Target ALS Foundation) FS-2023-SBF-S6U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) NS074324U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) NS089616U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) NS098243U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) NS110098U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) NS128494
6 · The paper itself

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.

Indexed as

Adaptor Proteins, Signal TransducingAutophagy-Related ProteinsCell Cycle ProteinsLipid MetabolismNeurodegenerative DiseasesAmyotrophic Lateral SclerosisAnimalsFrontotemporal DementiaHumansInduced Pluripotent Stem CellsMiceMutationNeuronsProteotoxic StressAdaptor Proteins, Signal TransducingAutophagy-Related ProteinsCell Cycle ProteinsUBQLN2 protein, human

Identifiers

PMID41912662
PMCPMC13058728

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.