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

Lysosomal dysfunction causes microglia-specific epigenetic and transcriptional changes linked to neurodegenerative diseases, with a significant impact observed in Sgsh-deficient mice.

• Why it matters: Understanding how lysosomal stress influences microglia is crucial because these changes are associated with neurodegeneration in both genetic and age-related conditions, yet the underlying mechanisms remain unclear.
• What they did: The study used a mouse model of mucopolysaccharidosis type IIIA, employing imaging, transcriptomic, and epigenetic analyses to identify microglia as the most affected cell type and to uncover key transcription factors involved in disease-related changes.
• The result: Findings demonstrate that lysosomal stress activates specific transcriptional programs involving MITF/TFE and other factors, which are also present in models of age-related neurodegeneration and human Alzheimer's disease, highlighting shared disease mechanisms.