This study investigated how lysosomal dysfunction shapes microglial identity, using a mouse model of mucopolysaccharidosis type IIIA (MPS IIIA, caused by SGSH deficiency) to map transcriptomic and epigenetic changes in microglia, and compared findings to mouse models of age-related neurodegeneration and human Alzheimer's disease (AD) brain tissue.
Microglia were the most profoundly affected cell type in SGSH-deficient brains. MITF/TFE family transcription factors were identified as dominant drivers of lysosomal stress–induced epigenetic and transcriptional reprogramming in microglia, acting collaboratively with AP-1/ATF, C/EBP, and PU.1/ETS factors. The resulting disease-associated microglia (DAM) signature overlapped with that seen in age-related neurodegeneration models and human AD patients.
Findings rely primarily on a single lysosomal storage disorder model (MPS IIIA); causal validation in human AD tissue is limited by the cross-sectional, correlative nature of that comparison. The study is conducted in mice for most mechanistic work, with inherent species-translation caveats.
Lysosomal stress via MITF/TFE-driven pathways may be a shared upstream mechanism across multiple neurodegenerative diseases; targeting this pathway could be a tractable strategy worth exploring in therapeutic development for AD and related disorders.
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