Retinal oxidation, apoptosis and age- and sex-differences in the mnd mutant mouse, a model of neuronal ceroid lipofuscinosis

Guarneri, Rosa; Russo, Domenica; Cascio, Caterina; D’Agostino, Stefania; Galizzi, Giacoma; Bigini, Paolo; Mennini, Tiziana; Guarneri, P.

doi:10.1016/j.brainres.2004.04.040

Cited by 32 publications

(18 citation statements)

References 60 publications

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“…This hallmark degeneration of the retina has been seen in other NCL animal models [44], [70], [71], [72], [73], [74], [75], [76]. Here we show that cell loss in the Cln6 nclf retina begins around 3 months of age and progresses rapidly.…”

Section: Discussionsupporting

confidence: 82%

A Murine Model of Variant Late Infantile Ceroid Lipofuscinosis Recapitulates Behavioral and Pathological Phenotypes of Human Disease

et al. 2013

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Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6nclf) mouse line to validate its utility for translational research. We demonstrate that this Cln6nclf mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6nclf mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics.

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Section: Discussionsupporting

confidence: 82%

A Murine Model of Variant Late Infantile Ceroid Lipofuscinosis Recapitulates Behavioral and Pathological Phenotypes of Human Disease

et al. 2013

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“…Unlike the rod photoreceptors of the Rds/Rds mouse~Sanyal & Jansen, 1981!, all three strains of the rd-3 homozygotes clearly are able to assemble OS discs, although they are not all normal in either size or orientation. In considering the overall pattern of cell loss, the rd-3/rd-3 degeneration shows no apparent preference for rods over cones or for center versus periphery and thus differs from the rd/rd mouse where rods are lost The TUNEL data show that photoreceptors die by apoptosis in this mutation as in every other retinal degeneration described to date, whether inherited~Chang et al, 1993b; Portera-Cailliau et al, 1994;Tso et al, 1994;Smith et al, 1995;Ikeda et al, 1999;Guarneri et al, 2004!, or induced~Shahinfar et al, 1991Cook et al, 1995!. In the murine retinal degenerations described above, the developmental stage at which the effect of the mutant genes becomes expressed varies widely. The earlier the onset, as in rd, the less mature the OS will be as photoreceptor cells begin to die en masse.…”

Section: Discussionmentioning

confidence: 86%

“…The ability of secondary genes or background to affect the severity of specific retinal inherited degenerations is now appreciated for a number of these allelic variations~Heckenlively et al., 1993a,b;Hawes et al, 1999;Messer et al, 1999;Mehalow et al, 2003;Guarneri et al, 2004!. This is also recognized as an important source of variance in families with respect to disease phenotype.…”

Section: Discussionmentioning

confidence: 99%

Morphological characterization of the retinal degeneration in three strains of mice carrying the rd-3 mutation

Fariss

Heckenlively

Farber³

et al. 2005

Vis Neurosci

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Retinal development in 3 strains of rd-3/rd-3 mutant mice, previously shown to have different rates of degeneration, was studied using light, electron, and immunofluorescence microscopy. The time course and phenotype of the degeneration as well as details on the mechanism of massive photoreceptor cell loss are compared with other known retinal degenerations in mice. Up until postnatal day (P) 10, the retinas of all three strains (RBF, 4Bnr, In-30) develop similarly to those of pigmented and nonpigmented controls. TUNEL-positive cells appear in the outer nuclear layer (ONL) by P14, and reach a maximum in all three mutant strains around P21. Scattered rods and cones form a loose, monolayered ONL by 8 weeks in the albino RBF strain, by 10 weeks in the albino 4Bnr strain, and by 16 weeks in the pigmented In-30 strain. Though the initial degeneration begins in the central retina, there is no preferred gradient of cell death between central and peripheral photoreceptors. Rods and cones are present at all ages examined. During development, stacks of outer segments (OS) form in all three strains though they never achieve full adult lengths, and often have disorganized, atypical OS. Rod opsin is expressed in the developing OS but is redistributed into plasma membrane as OS degeneration proceeds. Retinal pigment epithelial (RPE) cells of all mutant strains contain packets of phagocytosed OS, and their apical processes associate with the distal ends of the OS. At their synaptic sites, photoreceptor terminals contain ribbons apposed to apparently normal postsynaptic triads. As photoreceptors are lost, Müller cells fill in space in the ONL but they do not appear to undergo significant hypertrophy or migration, though during the degeneration, glial fibrillary acidic protein (GFAP) expression is gradually upregulated. Macrophage-like cells are found frequently in the subretinal space after the onset of photoreceptor apoptosis. As OS disappear, the RPE apical processes revert to simple microvilli. Late in the degeneration, some RPE cells die and neighboring cells appear to flatten as if to maintain confluence. In regions of RPE cell loss that happen to lie above retina where the ONL is gone, cells of the inner nuclear layer (INL), wrapped by Müller cell processes, may front directly on Bruch's membrane.

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“…There is some histological evidence from Cln3 and Cln8 mouse mutants that the balance between pro- and anti-oxidant molecules in brain sections changes with disease progression (52,56). Additionally, the levels of the anti-oxidant scavenger protein MnSOD are elevated in brain material from both Cln3 mutant mice (52) and Cln6 mutant sheep (57).…”

Section: Discussionmentioning

confidence: 99%

The Batten disease gene CLN3 is required for the response to oxidative stress

Tuxworth

Chen

Vivancos

et al. 2011

Human Molecular Genetics

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Mutations in the CLN3 gene cause juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), an early onset neurodegenerative disorder. JNCL is the most common of the NCLs, a group of disorders with infant or childhood onset that are caused by single gene mutations. The NCLs, although relatively rare, share many pathological and clinical similarities with the more common late-onset neurodegenerative disorders, while their simple genetic basis makes them an excellent paradigm. The early onset and rapid disease progression in the NCLs suggests that one or more key cellular processes are severely compromised. To identify the functional pathways compromised in JNCL, we have performed a gain-of-function modifier screen in Drosophila. We find that CLN3 interacts genetically with the core stress signalling pathways and components of stress granules, suggesting a function in stress responses. In support of this, we find that Drosophila lacking CLN3 function are hypersensitive to oxidative stress yet they respond normally to other physiological stresses. Overexpression of CLN3 is sufficient to confer increased resistance to oxidative stress. We find that CLN3 mutant flies perceive conditions of increased oxidative stress correctly but are unable to detoxify reactive oxygen species, suggesting that their ability to respond is compromised. Together, our data suggest that the lack of CLN3 function leads to a failure to manage the response to oxidative stress and this may be the key deficit in JNCL that leads to neuronal degeneration.

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Retinal oxidation, apoptosis and age- and sex-differences in the mnd mutant mouse, a model of neuronal ceroid lipofuscinosis

Cited by 32 publications

References 60 publications

A Murine Model of Variant Late Infantile Ceroid Lipofuscinosis Recapitulates Behavioral and Pathological Phenotypes of Human Disease

A Murine Model of Variant Late Infantile Ceroid Lipofuscinosis Recapitulates Behavioral and Pathological Phenotypes of Human Disease

Morphological characterization of the retinal degeneration in three strains of mice carrying the rd-3 mutation

The Batten disease gene CLN3 is required for the response to oxidative stress

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