{
  "abstract": "Lysosomal dysfunction is causally linked to neurodegeneration in many lysosomal storage disorders (LSDs) and is associated with various age-related neurodegenerative diseases 1,2 , but there is limited understanding of the mechanisms by which altered lysosomal function leads to changes in gene expression that drive pathogenic cellular phenotypes. To investigate this question, we performed systematic imaging, transcriptomic, and epigenetic studies of major brain cell types in Sgsh null (KO) mice, a preclinical mouse model for Sanfilippo syndrome (Mucopolysaccharidosis Type IIIA, MPS-IIIA) 3,4 . MPS-IIIA is a neurodegenerative LSD caused by homozygous loss-of-function (LoF) mutations in SGSH which results in severe early-onset developmental, behavioral, and neurocognitive impairment 5–15 . Electron microscopy, immunohistochemistry, and single-nucleus RNA-sequencing analysis revealed microglia as the cell type exhibiting the most dramatic phenotypic alterations in Sgsh KO mice. Further temporal analysis of microglia gene expression showed dysregulation of genes associated with lysosomal function and immune signaling pathways beginning early in the course of the disease. Sgsh deficiency similarly resulted in increases in open chromatin and histone acetylation at thousands of putative microglia-specific enhancers associated with upregulated genes but had much less impact on the epigenetic landscapes of neurons or oligodendrocytes. We provide evidence for 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 PU.1/ETS and C/EBP transcription factors. Lastly, we show that features of the transcriptomic and epigenetic alterations observed in murine Sgsh deficiency are also observed in microglia derived from mouse models of age-related neurodegeneration and in human Alzheimer’s disease patients, revealing common and disease-specific transcriptional mechanisms associated with disease-associated microglia phenotypes.",
  "abstract_shown": true,
  "affiliations": [
    "Department 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",
    "Department 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",
    "Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA",
    "Department 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",
    "Ionis Pharmaceuticals, Carlsbad, CA, USA",
    "Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA",
    "Ann 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",
    "Ann 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",
    "Department 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",
    "Ann 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",
    "Broad 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",
    "Department 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"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 21,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Christopher D. Balak",
      "orcid": "0000-0001-9149-5982"
    },
    {
      "affs": [
        1
      ],
      "name": "Johannes C. M. Schlachetzki",
      "orcid": "0000-0002-7801-9743"
    },
    {
      "affs": [
        2
      ],
      "name": "Addison J. Lana",
      "orcid": "0000-0002-2656-9209"
    },
    {
      "affs": [
        3
      ],
      "name": "Elizabeth West"
    },
    {
      "affs": [
        4
      ],
      "name": "Christine Hong"
    },
    {
      "affs": [
        4
      ],
      "name": "Jordan DuGal"
    },
    {
      "affs": [
        2
      ],
      "name": "Yi Zhou"
    },
    {
      "affs": [
        2
      ],
      "name": "Benjamin Li"
    },
    {
      "affs": [
        2
      ],
      "name": "Nathanael J. Spann",
      "orcid": "0000-0001-7828-6123"
    },
    {
      "affs": [
        2
      ],
      "name": "Payam A. Saisan",
      "orcid": "0009-0003-9422-7643"
    },
    {
      "affs": [
        5
      ],
      "name": "Vishal Sarsani",
      "orcid": "0000-0002-9272-3438"
    },
    {
      "affs": [
        6
      ],
      "name": "Kilian L. Kleemann",
      "orcid": "0000-0002-2753-6804"
    },
    {
      "affs": [
        7
      ],
      "name": "Xiaoming Zhang"
    },
    {
      "affs": [
        2
      ],
      "name": "Martina P. Pasillas",
      "orcid": "0000-0002-9337-0136"
    },
    {
      "affs": [
        2
      ],
      "name": "Sydney O’Brien"
    },
    {
      "affs": [
        2
      ],
      "name": "Juliette A. Bokor"
    },
    {
      "affs": [
        8
      ],
      "name": "Philip L.S.M. Gordts",
      "orcid": "0000-0001-7224-4328"
    },
    {
      "affs": [
        9
      ],
      "name": "Oleg Butovsky",
      "orcid": "0000-0003-0186-8867"
    },
    {
      "affs": [
        10
      ],
      "name": "Beth Stevens",
      "orcid": "0000-0003-4226-1201"
    },
    {
      "affs": [
        4
      ],
      "name": "Fredrik Kamme",
      "orcid": "0000-0003-2877-6954"
    },
    {
      "affs": [
        11
      ],
      "name": "Christopher K. Glass",
      "orcid": "0000-0003-4344-3592"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7ay5a7tmcbg9d.bib",
  "cited_by": 6,
  "doi": "10.1016/j.immuni.2026.07.008",
  "fulltext_url": null,
  "id": "7ay5a7tmcbg9d",
  "issns": [
    "1074-7613",
    "1097-4180"
  ],
  "landing_url": "https://doi.org/10.1016/j.immuni.2026.07.008",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2808|Neuroinflammation and Neurodegeneration Mechanisms"
    ]
  ],
  "openalex": "W7172337217",
  "pdf_url": null,
  "pmcid": "PMC11601307",
  "pmid": "39605454",
  "published": "2026-08-01",
  "publisher": "Cell Press",
  "ris": "https://research.draconitic.com/paper/7ay5a7tmcbg9d.ris",
  "sources": [
    {
      "first_seen": "2026-11-05T13:21:03Z",
      "native_id": "W7172337217",
      "source": "openalex",
      "url": "https://doi.org/10.1016/j.immuni.2026.07.008"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2808|Neuroinflammation and Neurodegeneration Mechanisms",
      "subfield": "neurology"
    }
  ],
  "title": "Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases",
  "title_text": "Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T13:20:36Z",
  "url": "https://research.draconitic.com/paper/7ay5a7tmcbg9d",
  "venue": "Immunity",
  "versions": []
}