Journal Article

DZNE-2024-01276

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover.

Yasa, S. ; Butz, E.Extern* ; Colombo, A. V.DZNE* ; Chandrachud, U. ; Montore, L. ; Tschirner, S.DZNE* ; Prestel, M.DZNE* ; Sheridan, S. D. ; Müller, S. A.DZNE* ; Groh, J.Extern* ; Lichtenthaler, S. F.DZNE* ; Tahirovic, S.DZNE* ; Cotman, S. L.

2024
Springer Nature London

This record in other databases:    

Please use a persistent id in citations: doi:10.1038/s42003-024-07057-w

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.

Keyword(s): Animals (MeSH) ; Microglia: metabolism (MeSH) ; Microglia: pathology (MeSH) ; Membrane Glycoproteins: metabolism (MeSH) ; Membrane Glycoproteins: genetics (MeSH) ; Lipid Metabolism (MeSH) ; Mice (MeSH) ; Molecular Chaperones: metabolism (MeSH) ; Molecular Chaperones: genetics (MeSH) ; Myelin Sheath: metabolism (MeSH) ; Neuronal Ceroid-Lipofuscinoses: metabolism (MeSH) ; Neuronal Ceroid-Lipofuscinoses: genetics (MeSH) ; Neuronal Ceroid-Lipofuscinoses: pathology (MeSH) ; Mice, Knockout (MeSH) ; Lysosomes: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; Autophagy (MeSH) ; Membrane Glycoproteins ; CLN3 protein, mouse ; Molecular Chaperones

---

Contributing Institute(s):

1. Juvenile Neurodegeneration (AG Tahirovic)
2. Neuroproteomics (AG Lichtenthaler)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

---

Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

---

---

Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dataset Müller, S. A.DZNE* ; Lichtenthaler, S.DZNE*
Dataset: Proteomics of CLN3-deficient murine microglia identifies a disease associated phenotype with lysosomal alterations
PRoteomics IDEntifications Database (2024)2024   Fulltext BibTeX | EndNote: XML, Text | RIS

---