TY  - JOUR
AU  - Yasa, Seda
AU  - Butz, Elisabeth
AU  - Colombo, Alessio Vittorio
AU  - Chandrachud, Uma
AU  - Montore, Luca
AU  - Tschirner, Sarah
AU  - Prestel, Matthias
AU  - Sheridan, Steven D
AU  - Müller, Stephan A
AU  - Groh, Janos
AU  - Lichtenthaler, Stefan F
AU  - Tahirovic, Sabina
AU  - Cotman, Susan L
TI  - Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover.
JO  - Communications biology
VL  - 7
IS  - 1
SN  - 2399-3642
CY  - London
PB  - Springer Nature
M1  - DZNE-2024-01276
SP  - 1373
PY  - 2024
AB  - 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.
KW  - Animals
KW  - Microglia: metabolism
KW  - Microglia: pathology
KW  - Membrane Glycoproteins: metabolism
KW  - Membrane Glycoproteins: genetics
KW  - Lipid Metabolism
KW  - Mice
KW  - Molecular Chaperones: metabolism
KW  - Molecular Chaperones: genetics
KW  - Myelin Sheath: metabolism
KW  - Neuronal Ceroid-Lipofuscinoses: metabolism
KW  - Neuronal Ceroid-Lipofuscinoses: genetics
KW  - Neuronal Ceroid-Lipofuscinoses: pathology
KW  - Mice, Knockout
KW  - Lysosomes: metabolism
KW  - Mice, Inbred C57BL
KW  - Autophagy
KW  - Membrane Glycoproteins (NLM Chemicals)
KW  - CLN3 protein, mouse (NLM Chemicals)
KW  - Molecular Chaperones (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39438652
C2  - pmc:PMC11496662
DO  - DOI:10.1038/s42003-024-07057-w
UR  - https://pub.dzne.de/record/272858
ER  -