title: Cln5-deficiency in mice leads to microglial activation, defective myelination and changes in lipid metabolism.
abstract: CLN5 disease, late infantile variant phenotype neuronal ceroid lipofuscinosis, is a severe neurodegenerative disease caused by mutations in the CLN5 gene, which encodes a lysosomal protein of unknown function. Cln5-deficiency in mice leads to loss of thalamocortical neurons, and glial activation, but the underlying mechanisms are poorly understood. We have now studied the gene expression of Cln5 in the mouse brain and show that it increases gradually with age and differs between neurons and glia, with the highest expression in microglia. In Cln5(-/-) mice, we documented early and significant microglial activation that was already evident at 3 months of age. Loss of Cln5 also leads to defective myelination in vitro and in the developing mouse brain. This was accompanied by early alterations in serum lipid profiles, dysfunctional cellular metabolism and lipid transport in Cln5(-/-) mice. Taken together, these data provide significant new information about events associated with Cln5-deficiency, revealing altered myelination and disturbances in lipid metabolism, together with an early neuroimmune response.
authors.affiliation: National Institute for Health and Welfare (THL), Public Health Genomics Unit, Helsinki, Finland.
authors.forename: Mia-Lisa
authors.initials: ML
authors.lastname: Schmiedt
authors.forename: Tea
authors.initials: T
authors.lastname: Blom
authors.forename: Tomas
authors.initials: T
authors.lastname: Blom
authors.forename: Outi
authors.initials: O
authors.lastname: Kopra
authors.forename: Andrew
authors.initials: A
authors.lastname: Wong
authors.forename: Carina
authors.initials: C
authors.lastname: von Schantz-Fant
authors.forename: Elina
authors.initials: E
authors.lastname: Ikonen
authors.forename: Mervi
authors.initials: M
authors.lastname: Kuronen
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Anu
authors.initials: A
authors.lastname: Jalanko
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D052439:Lipid Metabolism Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051907:Lysosomal Membrane Proteins; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology
chemical_list: C488572:Cln5 protein, mouse; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins