Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

Katz, Martin L.; Johnson, Gary S.; Tullis, Gregory E.

doi:10.1016/j.nbd.2007.08.017

Cited by 32 publications

(38 citation statements)

References 34 publications

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“…In most NCL forms, subunit c of the mitochondrial ATP synthase is the dominant protein component of inclusions. In JNCL mouse models, ceroid is evident in neuronal populations of the brain and retina (12,28), as well as in hepatocytes (12). We observed significant autofluorescent inclusions in the kidneys of Cln3 lacZ/lacZ mice, but not in age-matched controls.…”

Section: Discussionmentioning

confidence: 67%

Osmoregulation of ceroid neuronal lipofuscinosis type 3 in the renal medulla

Stein¹,

Yancey

Martins³

et al. 2010

American Journal of Physiology-Cell Physiology

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Recessive inheritance of mutations in ceroid neuronal lipofuscinosis type 3 (CLN3) results in juvenile neuronal ceroid lipofuscinosis (JNCL), a childhood neurodegenerative disease with symptoms including loss of vision, seizures, and motor and mental decline. CLN3p is a transmembrane protein with undefined function. Using a Cln3 reporter mouse harboring a nuclear-localized bacterial beta-galactosidase (beta-Gal) gene driven by the native Cln3 promoter, we detected beta-Gal most prominently in epithelial cells of skin, colon, lung, and kidney. In the kidney, beta-Gal-positive nuclei were predominant in medullary collecting duct principal cells, with increased expression along the medullary osmotic gradient. Quantification of Cln3 transcript levels from kidneys of wild-type (Cln3(+/+)) mice corroborated this expression gradient. Reporter mouse-derived renal epithelial cultures demonstrated a tonicity-dependent increase in beta-Gal expression. RT-quantitative PCR determination of Cln3 transcript levels further supported osmoregulation at the Cln3 locus. In vivo, osmoresponsiveness of Cln3 was demonstrated by reduction of medullary Cln3 transcript abundance after furosemide administration. Primary cultures of epithelial cells of the inner medulla from Cln3(lacZ/lacZ) (CLN3p-null) mice showed no defect in osmolyte accumulation or taurine flux, arguing against a requirement for CLN3p in osmolyte import or synthesis. CLN3p-deficient mice with free access to water showed a mild urine-concentrating defect but, upon water deprivation, were able to concentrate their urine normally. Unexpectedly, we found that CLN3p-deficient mice were hyperkalemic and had a low fractional excretion of K(+). Together, these findings suggest an osmoregulated role for CLN3p in renal control of water and K(+) balance.

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Section: Discussionmentioning

confidence: 67%

Osmoregulation of ceroid neuronal lipofuscinosis type 3 in the renal medulla

Stein¹,

Yancey

Martins³

et al. 2010

American Journal of Physiology-Cell Physiology

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“…Indeed, optic nerve degeneration has been reported in mouse models of the NCLs. 15,31,32 In the affected Dachshund, disease-specific storage body accumulation was observed in ganglion cells, cells of the inner nuclear layer, and in the photoreceptor cells at 10.5 months of age (Figs. 6, 7).…”

Section: Discussionmentioning

confidence: 99%

“…In some cases, NCL gene mutations in mice result in only modest phenotypic signs of neurodegeneration. 15 Naturally occurring NCLs have been identified in several larger animal species, including dogs. 16 -21 Among the canine NCLs is a form of the disease in Dachshunds that results from a mutation in TPP1 that encodes the lysosomal enzyme tripeptidyl peptidase 1.…”

mentioning

confidence: 99%

Retinal Pathology in a Canine Model of Late Infantile Neuronal Ceroid Lipofuscinosis

Katz

Coates

Cooper

et al. 2008

Invest. Ophthalmol. Vis. Sci.

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“…32 Effects of the disruption of Cln3 gene in mice is less severe than in humans, as revealed by phenotypic analyses of mouse gene knockout models. WT mice lived for 135 weeks, compared to 107 weeks for Cln3 Δex7/8 mice.…”

Section: Galcer and Neuronal Cell Countsmentioning

confidence: 99%

Exogenous Galactosylceramide as Potential Treatment for CLN3 Disease

El-Sitt

Soueid

Maalouf

et al. 2019

Annals of Neurology

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Objective: CLN3 disease is the commonest of the neuronal ceroid lipofuscinoses, a group of pediatric neurodegenerative disorders. Functions of the CLN3 protein include antiapoptotic properties and facilitating anterograde transport of galactosylceramide from Golgi to lipid rafts. This study confirms the beneficial effects of long-term exogenous galactosylceramide supplementation on longevity, neurobehavioral parameters, neuronal cell counts, astrogliosis, and diminution in brain and serum ceramide levels in Cln3 Δex7/8 knock-in mice. Additionally, the impact of galactosylceramide on ceramide synthesis enzymes is documented. Methods: A group of 72 mice received galactosylceramide or vehicle for 40 weeks. The effect of galactosylceramide supplementation on Cln3 Δex7/8 mice was determined by performing behavioral tests, measuring ceramide in brains and serum, and assessing impact on longevity, subunit C storage, astrogliosis, and neuronal cell counts. Results: Galactosylceramide resulted in enhanced grip strength of forelimbs in male and female mice, better balance on the accelerating rotarod in females, and improved motor coordination during pole climbing in male mice. Brain and serum ceramide levels as well as apoptosis rates were lower in galactosylceramide-treated Cln3 Δex7/8 mice. Galactosylceramide also increased neuronal cell counts significantly in male and female mice and tended to decrease subunit C storage in specific brain regions. Astrogliosis dropped in females compared to a slight increase in males after galactosylceramide. Galactosylceramide increased the lifespan of affected mice. Interpretation: Galactosylceramide improved behavioral, neuropathological, and biochemical parameters in Cln3 Δex7/8 mice, paving the way for effective therapy for CLN3 disease and use of serum ceramide as a potential biomarker to track impact of therapies.

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Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

Cited by 32 publications

References 34 publications

Osmoregulation of ceroid neuronal lipofuscinosis type 3 in the renal medulla

Osmoregulation of ceroid neuronal lipofuscinosis type 3 in the renal medulla

Retinal Pathology in a Canine Model of Late Infantile Neuronal Ceroid Lipofuscinosis

Exogenous Galactosylceramide as Potential Treatment for CLN3 Disease

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