Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases
12 affiliations
- 1Department 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
- 2Department 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
- 3Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
- 4Department 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
- 5Ionis Pharmaceuticals, Carlsbad, CA, USA
- 6Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- 7Ann 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
- 8Ann 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
- 9Department 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
- 10Ann 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
- 11Broad 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
- 12Department 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: [email protected]
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.
Related
- The pathological roles of intrinsically disordered proteins in lysosomal acidification dysfunction in neurodegenerative diseases.
- Single-Cell Dissection of Microglial Dysfunction in Diabetes-Associated Neurodegenerative Vulnerability.
- Nanomaterial modulation of lysosomal homeostasis in neurodegenerative proteinopathies: from pathological-protein degradation to re-release and seeding
- Dysfunction of lipid metabolism and lysosomal capacity: at the core of microglial aging?
- Autophagy–Gut Microbiota–Epigenetic Interactions in Disease Pathogenesis: Focus on Neurodegenerative and Neuropsychiatric Disorders and Therapeutic Perspectives
BibTeX
@article{balak2026lysosomal,
title = {{Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases}},
author = {Christopher D. Balak and Johannes C. M. Schlachetzki and Addison J. Lana and Elizabeth West and Christine Hong and Jordan DuGal and Yi Zhou and Benjamin Li and Nathanael J. Spann and Payam A. Saisan and Vishal Sarsani and Kilian L. Kleemann and Xiaoming Zhang and Martina P. Pasillas and Sydney O’Brien and Juliette A. Bokor and Philip L.S.M. Gordts and Oleg Butovsky and Beth Stevens and Fredrik Kamme and Christopher K. Glass},
journal = {Immunity},
year = {2026},
month = aug,
doi = {10.1016/j.immuni.2026.07.008},
url = {https://doi.org/10.1016/j.immuni.2026.07.008},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases
AU - Christopher D. Balak
AU - Johannes C. M. Schlachetzki
AU - Addison J. Lana
AU - Elizabeth West
AU - Christine Hong
AU - Jordan DuGal
AU - Yi Zhou
AU - Benjamin Li
AU - Nathanael J. Spann
AU - Payam A. Saisan
AU - Vishal Sarsani
AU - Kilian L. Kleemann
AU - Xiaoming Zhang
AU - Martina P. Pasillas
AU - Sydney O’Brien
AU - Juliette A. Bokor
AU - Philip L.S.M. Gordts
AU - Oleg Butovsky
AU - Beth Stevens
AU - Fredrik Kamme
AU - Christopher K. Glass
PY - 2026
DA - 2026/08/01
JO - Immunity
DO - 10.1016/j.immuni.2026.07.008
UR - https://doi.org/10.1016/j.immuni.2026.07.008
AB - 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.
SN - 1074-7613
SN - 1097-4180
ER -