BioProject

Both CLN1 and CLN5 deficiency leads to severe neurodegenerative diseases of childhood, known as neuronal ceroid lipofuscinoses (NCL). More...

Both CLN1 and CLN5 deficiency leads to severe neurodegenerative diseases of childhood, known as neuronal ceroid lipofuscinoses (NCL). The broadly similar phenotypes of NCL mouse models, and the potential for interactions between NCL proteins, raise the possibility of shared or converging disease mechanisms. To begin addressing these issues we have developed a novel mouse model lacking both Cln1 and Cln5 genes. These Cln1/5 double knock-out (Cln1/5 dko) mice were fertile, showing a slight decrease in expected Mendelian breeding ratios, as well as impaired embryoid body formation of induced pluripotent stem cells derived from Cln1/5 dko fibroblasts. Typical manifestations of the NCL diseases, seizures and motor dysfunction, were detected at the age of 3 months, earlier than in either single knock-out mouse. Pathological analyses revealed a similar exacerbation and earlier onset of disease in Cln1/5 dko mice, which exhibit a pronounced accumulation of autofluorescent storage material. Cortical demyelination and more pronounced glial activation in cortical and thalamic regions was followed by cortical neuron loss. Alterations in lipid metabolism in Cln1/5 dko showed specifically an increase in serum phospholipid transfer protein (PLTP) activity. Finally, gene expression profiling of Cln1/5 dko cortex revealed defects in myelination and immune response pathways, with a prominent downregulation of alpha-synuclein in Cln1/5 dko mouse brains. The simultaneous loss of both Cln1 and Cln5 genes may enhance the typical pathological phenotypes of these mice by disrupting down shared or convergent pathogenic pathways, which may potentially include interactions of CLN1 and CLN5. Overall design: Basic characterization of Cln1/5 double knock-out mouse model. Aim was to find possible differentially expressed genes and up-or downregulated pathways in Cln1/5 double knock-out vs. wild-type mouse cortex. Total RNA isolated from 1 month old Cln1-/-/Cln5-/- mouse cortex. Less...