Cln5-deficiency in mice leads to microglial activation, defective myelination and changes in lipid metabolism

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.