CLN5
Ceroid-lipofuscinosis neuronal protein 5 (Protein CLN5) [Contains: Ceroid-lipofuscinosis neuronal protein 5, secreted form]
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Both CLN1 and CLN5 deficiencies lead to severe neurodegenerative diseases of childhood, known as neuronal ceroid lipofuscinoses (NCLs). The broadly similar phenotypes of NCL mouse models, and the potential for interactions between NCL proteins, raise the possibility of shared or convergent disease mechanisms. To begin addressing these issues, we have developed a new mouse model lacking both Cln1 and Cln5 genes. These double-knockout (Cln1/5 dko) mice were fertile, showing a slight decrease in expected Mendelian breeding ratios, as well as impaired embryoid body formation by induced pluripotent stem cells derived from Cln1/5 dko fibroblasts. Typical disease manifestations of the NCLs, i.e. seizures and motor dysfunction, were detected at the age of 3 months, earlier than in either single knockout mouse. Pathological analyses revealed a similar exacerbation and earlier onset of disease in Cln1/5 dko mice, which exhibited 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 a specific increase in plasma 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 α-synuclein in Cln1/5 dko mouse brains. The simultaneous loss of both Cln1 and Cln5 genes might enhance the typical pathological phenotypes of these mice by disrupting or downregulating shared or convergent pathogenic pathways, which could potentially include interactions of CLN1 and CLN5.
MeSH Terms
- Aging
- Animals
- Cell Differentiation
- Cerebral Cortex
- Embryoid Bodies
- Female
- Fluorescence
- Gene Expression Profiling
- Gliosis
- Immunity
- Induced Pluripotent Stem Cells
- Lysosome-Associated Membrane Glycoproteins
- Membrane Glycoproteins
- Mice
- Mice, Knockout
- Myelin Sheath
- Neuronal Ceroid-Lipofuscinoses
- Neurons
- Phenotype
- Phospholipid Transfer Proteins
- Phospholipids
- Thiolester Hydrolases
- alpha-Synuclein
Neuronal ceroid lipofuscinoses (NCL) comprise the most common group of childhood encephalopathies caused by mutations in eight genetic loci, CLN1-CLN8. Here, we have developed a novel mouse model for the human vLINCL (CLN5) by targeted deletion of exon 3 of the mouse Cln5 gene. The Cln5-/- mice showed loss of vision and accumulation of autofluorescent storage material in the central nervous system (CNS) and peripheral tissues without prominent brain atrophy. The ultrastructure of the storage material accurately replicated the abnormalities in human patients revealing mixture of lamellar profiles including fingerprint profiles as well as curvilinear and rectilinear bodies in electronmicroscopic analysis. Prominent loss of a subset of GABAergic interneurons in several brain areas was seen in the Cln5-/- mice. Transcript profiling of the brains of the Cln5-/- mice revealed altered expression in several genes involved in neurodegeneration, as well as in defense and immune response, typical of age-associated changes in the CNS. Downregulation of structural components of myelin was detected and this agrees well with the hypomyelination seen in the human vLINCL patients. In general, the progressive pathology of the Cln5-/- brain mimics the symptoms of the corresponding neurodegenerative disorder in man. Since the Cln5-/- mice do not exhibit significant brain atrophy, these mice could serve as models for studies on molecular processes associated with advanced aging.
MeSH Terms
- Aging
- Animals
- Base Sequence
- Brain
- DNA Primers
- Disease Models, Animal
- Gene Expression Profiling
- Humans
- Immunohistochemistry
- Lysosome-Associated Membrane Glycoproteins
- Lysosomes
- Membrane Proteins
- Mice
- Mice, Knockout
- Neuronal Ceroid-Lipofuscinoses
- Reverse Transcriptase Polymerase Chain Reaction
- gamma-Aminobutyric Acid