Lysosomal dysfunction drives a transcriptional and epigenetic signature found in disease-associated microglia in neurodegenerative diseases
Year: 2026
Type: article
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.
Source: Immunity
Authors: 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, Vishal Sarsani, Kilian L. Kleemann, Xiaoming Zhang, Martina P. Pasillas, Sydney O’Brien, Juliette A. Bokor, Philip L.S.M. Gordts, Oleg Butovsky, Beth Stevens, Fredrik Kamme, Christopher K. Glass
Institutions: University of California San Diego, Ionis Pharmaceuticals (United States), Broad Institute, Brigham and Women's Hospital, Harvard University, University Hospital Bonn, Tongji University, University of Utah, Massachusetts General Hospital, Boston Children's Hospital, Howard Hughes Medical Institute, Massachusetts Institute of Technology
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Funders: National Science Foundation, California Institute for Regenerative Medicine, Alzheimer's Association, JPB Foundation, Cure Alzheimer's Fund, Sanfilippo Children's Foundation, National Institutes of Health, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: Illumina NovaSeq 6000 Sequencing System, University of California San Diego Neuroscience Microscopy Imaging Core, Perturbing the LXR/SREBP axis to decipher protective and pathogenic AD/ADRD microglial phenotypes, Training Program in Basic and Clinical Genetics, JEOL JEM-1400Plus Transmission Electron Microscope, Mechanisms controlling human microglia gene expression
OpenAlex ID: W7172337217