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

Christopher D Balak1, Johannes C M Schlachetzki2, Addison J Lana3

  • 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.

Immunity
|August 3, 2026
PubMed

Insights

Lysosomal dysfunction impacts microglia, driving neurodegeneration. Transcription factors like MITF/TFE orchestrate these changes, common in storage disorders and Alzheimer's disease.

Area of Science:

  • Neurobiology
  • Cellular Biology
  • Genetics

Background:

  • Lysosomal dysfunction is a key factor in neurodegenerative diseases, including lysosomal storage disorders and age-related conditions.
  • Microglia, the brain's immune cells, are increasingly recognized for their role in neuroinflammation and neurodegeneration.

Purpose of the Study:

  • To investigate the cellular and molecular mechanisms underlying neurodegeneration caused by lysosomal dysfunction.
  • To identify the specific cell types and transcriptional pathways affected by lysosomal stress in the brain.

Main Methods:

  • Utilized a mouse model of mucopolysaccharidosis type IIIA (Sgsh deficiency).
  • Conducted systematic imaging, transcriptomic, and epigenetic analyses of brain tissue.
  • Investigated the roles of MITF/TFE family transcription factors and their collaborators.

Main Results:

  • Microglia were identified as the most profoundly affected cell type in Sgsh-deficient mice.
  • Lysosomal stress induced significant microglia-specific epigenetic and transcriptional changes, driven by MITF/TFE family members.
  • These alterations involved collaborative interactions with AP-1/ATF, C/EBP, and PU.1/ETS transcription factors.
  • Similar transcriptional and epigenetic features were observed in microglia from models of age-related neurodegeneration and human Alzheimer's disease.

Conclusions:

  • Lysosomal dysfunction profoundly impacts microglia, contributing to neurodegeneration.
  • MITF/TFE transcription factors play a critical role in mediating microglia responses to lysosomal stress.
  • Common and disease-specific mechanisms link lysosomal dysfunction to disease-associated microglia phenotypes in both storage disorders and age-related neurodegenerative diseases.
Keywords:
ChIP-seqMITFMPS-IIIATFE3disease-associated microgliaepigeneticslysosomal storage disorderlysosomemicroglianeurodegeneration

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