Evidence map›Paper›PMID 42546694›Full record

ArticleImmunity2026

Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases.

Christopher D Balak, Johannes C M Schlachetzki, Addison J Lana, Elizabeth West, Christine Hong, Jordan DuGal, Yi Zhou, Benjamin Li, Nathanael J Spann, Payam Saisan and 11 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Immunity, 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

21 authors.

Christopher D BalakDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA.
Johannes C M SchlachetzkiDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
Addison J LanaDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Elizabeth WestDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Biological Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA.
Christine HongIonis Pharmaceuticals, Carlsbad, CA, USA.
Jordan DuGalIonis Pharmaceuticals, Carlsbad, CA, USA.
Yi ZhouDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Benjamin LiDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Nathanael J SpannDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Payam SaisanDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Vishal SarsaniBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Kilian L KleemannAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
Xiaoming ZhangAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, China.
Martina P PasillasDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Sydney O'BrienDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Juliette A BokorDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Philip L S M GordtsDepartment of Medicine, University of California, San Diego, La Jolla, CA, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA; Department of Pathology, University of Utah, Salt Lake City, UT, USA.
Oleg ButovskyAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA.
Beth StevensBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Fredrik KammeIonis Pharmaceuticals, Carlsbad, CA, USA.
Christopher K GlassDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: ckg@ucsd.edu.

Funding

U of Calif, San Diego Neuroscience Microscopy ImagingP30NS047101 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GLEESON, JOSEPH G, ZHENG, BINHAI · 2003 to 2022
$9.0M
Training Program in Basic Clinical GeneticsT32GM008666 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI HAMILTON, BRUCE A · 1998 to 2021
$8.6M
Mechanisms controlling human microglia gene expressionR01NS096170 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GLASS, CHRISTOPHER K · 2016 to 2025
$4.3M
Perturbing the LXR/SREBP axis to decipher protective and pathogenic AD/ADRD microglial phenotypesRF1AG083977 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI COUFAL, NICOLE GABRIELE, GLASS, CHRISTOPHER K · 2024 to 2024
$3.8M
Illumina NovaSeq 6000 Sequencing SystemS10OD026929 · OD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI JEPSEN, KRISTEN LYNN · 2019 to 2019
$600k
JEOL JEM-1400Plus Transmission Electron MicroscopeS10OD023527 · OD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI FARQUHAR, MARILYN GIST · 2017 to 2017
$579k
NIA NIH HHS RF1 AG083977NIGMS NIH HHS T32 GM008666NIH HHS S10 OD023527NIH HHS S10 OD026929NINDS NIH HHS P30 NS047101NINDS NIH HHS R01 NS096170
6 · The paper itself

Abstract

Lysosomal dysfunction is causally linked to neurodegeneration in many lysosomal storage disorders and is associated with various age-related neurodegenerative diseases. Here, we investigated the question of underlying mechanisms using a mouse model of mucopolysaccharidosis type IIIA caused by deficiency of the lysosomal hydrolase SGSH. Systematic imaging and transcriptomic and epigenetic studies revealed microglia to be the most profoundly impacted cell type in brains of Sgsh-deficient mice. Further investigation identified dominant and context-dependent roles of members of the MITF/TFE family as major drivers of microglia-specific epigenetic and transcriptional changes resulting from lysosomal stress that are dependent on collaborative interactions with AP-1/ATF, C/EBP, and PU.1/ETS transcription factors. Features of the transcriptomic and epigenetic alterations observed in murine Sgsh deficiency were also observed in microglia derived from mouse models of age-related neurodegeneration and in human Alzheimer's disease patients. These findings reveal common and disease-specific transcriptional mechanisms associated with disease-associated microglia phenotypes.

Indexed as

Epigenesis, GeneticLysosomesMicrogliaNeurodegenerative DiseasesAnimalsBrainDisease Models, AnimalHumansMiceMice, KnockoutTranscription, GeneticTranscriptomeChIP-seqdisease-associated microgliaepigeneticslysosomal storage disorderlysosomemicrogliaMITFMPS-IIIAneurodegenerationTFE3

Identifiers

PMID42546694
PMCPMC13510288

What OpenQuestion holds

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Registered trials

None linked

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.