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Exacerbated neuronal ceroid lipofuscinosis phenotype in Cln1/5 double-knockout mice.

ABSTRACT: 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 ?-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.

SUBMITTER: Blom T

PROVIDER: S-EPMC3597017 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Exacerbated neuronal ceroid lipofuscinosis phenotype in Cln1/5 double-knockout mice.

Blom Tea T Schmiedt Mia-Lisa ML Wong Andrew M AM Kyttälä Aija A Soronen Jarkko J Jauhiainen Matti M Tyynelä Jaana J Cooper Jonathan D JD Jalanko Anu A

Disease models & mechanisms 20121012 2

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 ex ...[more]

PMID: 23065637

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Project description:Neuronal ceroid lipofuscinosis type1(CLN1), is a one form of the group of neuronal ceroid lipofuscinoses (NCLs), which is a neurodegenerative disorder characterized by progressive psychomotor deterioration, ataxia, epilepsy, and visual impairment. Neurological manifestations occur at a wide range of ages, from infancy to adulthood, but are most common in infancy. The prevalence of CLN1 is unclear; however, it is very rare in Japan and Europe. In Japan, only a few cases have been reported, two of infantile- and one of juvenile-onset type. Nonetheless, the clinical characteristics of Japanese patients and their relationship with the genotype have not been sufficiently investigated. Here, we report the cases of two siblings that presented with juvenile-onset (a 22-year-old man and a 29-year-old woman) CLN1 associated with type II diabetes mellitus. In both cases, visual impairment followed by learning disability was observed from school-age, and retinitis pigmentosa was noted on ophthalmological examination. These patients presented type II diabetes mellitus during their later teenage years. Brain magnetic resonance imaging (MRI) revealed marked atrophy of the cerebrum and cerebellum. The clinical symptoms lead to suspect NCLs. Decreased PPT1 enzyme activity in dried blood spot (DBS)and leukocytes were observed, and the genetic analysis revealed heterozygous missense variants in PPT1, c.550G > A/c.664 A > G (p. Glu184Lys/p. Lys216Glu). The latter variant of this patients was novel variant. The residual enzymatic activity of PPT1 in these cases is higher than that in the infantile type. CLN1 mutant cells are known to have altered subcellular expression and localization, enhanced lipid raft-mediated endocytosis, abnormal autophagy, and mitochondrial dysfunction. Although the prevalence of diabetes mellitus is high and the possibility of coincidental complications cannot be ruled out, we concluded that mitochondrial abnormalities are involved in insulin resistance and may be implicated in the development of type II diabetes mellitus. Further studies are needed to prove the correlation between CLN1 and diabetes mellitus.

Project description:BackgroundCeroid lipofuscinosis type 8 belongs to a heterogenous group of vision and life-threatening neurodegenerative diseases, neuronal ceroid lipofuscinosis (NCL). Effective therapy is limited to a single drug for treatment of ceroid lipofuscinosis type 2, necessitating animal disease models to facilitate further therapeutic development. Murine models are advantageous for therapeutic development due to easy genetic manipulation and rapid breeding, however appropriate genetic models need to be identified and characterized before being used for therapy testing. To date, murine models of ocular disease associated with ceroid lipofuscinosis type 8 have only been characterized in motor neuron degeneration mice.MethodsCln8-/- mice were produced by CRISPR/Cas9 genome editing through the International Mouse Phenotyping Consortium. Ophthalmic examination, optical coherence tomography, electroretinography, and ocular histology was performed on Cln8-/- mice and controls at 16 weeks of age. Quantification of all retinal layers, retinal pigmented epithelium, and the choriocapillaris was performed using images acquired with ocular coherence tomography and planimetry of histologic sections. Necropsy was performed to investigate concurrent systemic abnormalities. Clinical correlation with human patients with CLN8-associated retinopathy is provided.ResultsRetinal degeneration characterized by retinal pigment epithelium mottling, scattered drusen, and retinal vascular attenuation was noted in all Cln8-/- mice. Loss of inner and outer photoreceptor segment demarcation was noted on optical coherence tomography, with significant thinning of the whole retina (P=1e-9), outer nuclear layer (P=1e-9), and combined photoreceptor segments (P=1e-9). A global reduction in scotopic and photopic electroretinographic waveforms was noted in all Cln8-/- mice. Slight thickening of the inner plexiform layer (P=0.02) and inner nuclear layer (P=0.004), with significant thinning of the whole retina (P=0.03), outer nuclear layer (P=0.01), and outer photoreceptor segments (P=0.001) was appreciated on histologic sections. Scattered lipid vacuoles were noted in splenic red pulp of all Cln8-/- mice, though no gross systemic abnormalities were detected on necropsy. Retinal findings are consistent with those seen in patients with ceroid lipofuscinosis type 8.ConclusionsThis study provides detailed clinical characterization of retinopathy in adult Cln8-/- mice. Findings suggest that Cln8-/- mice may provide a useful murine model for development of novel therapeutics needed for treating ocular disease in patients with ceroid lipofuscinosis type 8.

Dataset Information

Exacerbated neuronal ceroid lipofuscinosis phenotype in Cln1/5 double-knockout mice.

Publications

Exacerbated neuronal ceroid lipofuscinosis phenotype in Cln1/5 double-knockout mice.

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