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@ARTICLE{Yasa:272858,
author = {Yasa, Seda and Butz, Elisabeth and Colombo, Alessio
Vittorio and Chandrachud, Uma and Montore, Luca and
Tschirner, Sarah and Prestel, Matthias and Sheridan, Steven
D and Müller, Stephan A and Groh, Janos and Lichtenthaler,
Stefan F and Tahirovic, Sabina and Cotman, Susan L},
title = {{L}oss of {CLN}3 in microglia leads to impaired lipid
metabolism and myelin turnover.},
journal = {Communications biology},
volume = {7},
number = {1},
issn = {2399-3642},
address = {London},
publisher = {Springer Nature},
reportid = {DZNE-2024-01276},
pages = {1373},
year = {2024},
abstract = {Loss-of-function mutations in CLN3 cause juvenile Batten
disease, featuring neurodegeneration and early-stage
neuroinflammation. How loss of CLN3 function leads to early
neuroinflammation is not yet understood. Here, we have
comprehensively studied microglia from Cln3∆ex7/8 mice, a
genetically accurate disease model. Loss of CLN3 function in
microglia leads to lysosomal storage material accumulation
and abnormal morphology of subcellular organelles. Moreover,
pathological proteomic signatures are indicative of defects
in lysosomal function and abnormal lipid metabolism.
Consistent with these findings, CLN3-deficient microglia are
unable to efficiently turnover myelin and metabolize the
associated lipids, showing defects in lipid droplet
formation and cholesterol accumulation. Accordingly, we also
observe impaired myelin integrity in aged Cln3∆ex7/8 mouse
brain. Autophagy inducers and cholesterol-lowering drugs
correct the observed microglial phenotypes. Taken together,
these data implicate a cell-autonomous defect in
CLN3-deficient microglia that impacts their ability to
support neuronal cell health, suggesting microglial targeted
therapies should be considered for CLN3 disease.},
keywords = {Animals / Microglia: metabolism / Microglia: pathology /
Membrane Glycoproteins: metabolism / Membrane Glycoproteins:
genetics / Lipid Metabolism / Mice / Molecular Chaperones:
metabolism / Molecular Chaperones: genetics / Myelin Sheath:
metabolism / Neuronal Ceroid-Lipofuscinoses: metabolism /
Neuronal Ceroid-Lipofuscinoses: genetics / Neuronal
Ceroid-Lipofuscinoses: pathology / Mice, Knockout /
Lysosomes: metabolism / Mice, Inbred C57BL / Autophagy /
Membrane Glycoproteins (NLM Chemicals) / CLN3 protein, mouse
(NLM Chemicals) / Molecular Chaperones (NLM Chemicals)},
cin = {AG Tahirovic / AG Lichtenthaler},
ddc = {570},
cid = {I:(DE-2719)1140003 / I:(DE-2719)1110006},
pnm = {352 - Disease Mechanisms (POF4-352)},
pid = {G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39438652},
pmc = {pmc:PMC11496662},
doi = {10.1038/s42003-024-07057-w},
url = {https://pub.dzne.de/record/272858},
}