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bioRxiv · 10.1101/2024.11.12.623296

Mechanisms driving epigenetic and transcriptional responses of microglia in a neurodegenerative lysosomal storage disorder model

Balak, C. D.·Schlachetzki, J. C. M.·Lana, A. J.·West, E.·Hong, C.·DuGal, J.·Zhou, Y.·Li, B.·Saisan, P.·Spann, N. J.·Sarsani, V.·Pasillas, M. P.·O'Brien, S.·Gordts, P.·Stevens, B.·Kamme, F.·Glass, C. K.
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Abstract

Lysosomal dysfunction is causally linked to neurodegeneration in many lysosomal storage disorders (LSDs) and is associated with various age-related neurodegenerative diseases1,2, 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 impairment5-15. 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 Alzheimers disease patients, revealing common and disease-specific transcriptional mechanisms associated with disease-associated microglia phenotypes.

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Balak, C. D., Schlachetzki, J. C. M., Lana, A. J., West, E., Hong, C., DuGal, J., Zhou, Y., Li, B., Saisan, P., Spann, N. J., Sarsani, V., Pasillas, M. P., O'Brien, S., Gordts, P., Stevens, B., Kamme, F., Glass, C. K.. 2024-11-14. Mechanisms driving epigenetic and transcriptional responses of microglia in a neurodegenerative lysosomal storage disorder model. https://doi.org/10.1101/2024.11.12.623296

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