Progression of early postnatal retinal pathology in a mouse model of neuronal ceroid lipofuscinosis

Seigel, Gail M.; Wagner, J; Wronska, Anetta; Campbell, Lauren; Ju, Weina; Zhong, Nanbert

doi:10.1038/sj.eye.6701770

Cited by 19 publications

(7 citation statements)

References 24 publications

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“…The motor neuron degeneration ( mnd ) mouse represents a naturally occurring animal model of CNL8 disease [ 57 ]. Similar to the nclf mouse, the mnd mouse harbors a mutation in a gene encoding a transmembrane protein of the ER [ 58 , 59 ] and displays progressive apoptotic degeneration of photoreceptor cells [ 57 , 60 – 62 ]. A recent study has analyzed the fate of intravitreally grafted neuralized mouse ES cells in this mutant, and observed wide-spread integration of the donor cells into the mnd retinas, where most of the cells acquired a neuronal phenotype.…”

Section: Discussionmentioning

confidence: 99%

Sustained Neural Stem Cell-Based Intraocular Delivery of CNTF Attenuates Photoreceptor Loss in the nclf Mouse Model of Neuronal Ceroid Lipofuscinosis

et al. 2015

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A sustained intraocular administration of neurotrophic factors is among the strategies aimed at establishing treatments for currently untreatable degenerative retinal disorders. In the present study we have analyzed the neuroprotective effects of a continuous neural stem (NS) cell-based intraocular delivery of ciliary neurotrophic factor (CNTF) on photoreceptor cells in the nclf mouse, an animal model of the neurodegenerative lysosomal storage disorder variant late infantile neuronal ceroid lipofuscinosis (vLINCL). To this aim, we genetically modified adherently cultivated NS cells with a polycistronic lentiviral vector encoding a secretable variant of CNTF together with a Venus reporter gene (CNTF-NS cells). NS cells for control experiments (control-NS cells) were modified with a vector encoding the reporter gene tdTomato. Clonal CNTF-NS and control-NS cell lines were established using fluorescent activated cell sorting and intravitreally grafted into 14 days old nclf mice at the onset of retinal degeneration. The grafted cells preferentially differentiated into astrocytes that were attached to the posterior side of the lenses and the vitreal side of the retinas and stably expressed the transgenes for at least six weeks, the latest post-transplantation time point analyzed. Integration of donor cells into host retinas, ongoing proliferation of grafted cells or adverse effects of the donor cells on the morphology of the host eyes were not observed. Quantitative analyses of host retinas two, four and six weeks after cell transplantation revealed the presence of significantly more photoreceptor cells in eyes with grafted CNTF-NS cells than in eyes with grafted control-NS cells. This is the first demonstration that a continuous intraocular administration of a neurotrophic factor attenuates retinal degeneration in an animal model of neuronal ceroid lipofuscinosis.

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Section: Discussionmentioning

confidence: 99%

Sustained Neural Stem Cell-Based Intraocular Delivery of CNTF Attenuates Photoreceptor Loss in the nclf Mouse Model of Neuronal Ceroid Lipofuscinosis

et al. 2015

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“…With regard to the retina, the majority of the mouse models tested so far show pathology primarily at the outer retina where the photoreceptors reside 9–13 . CLN6 deficient mice display the most robust retinal phenotype within the assessed NCL mouse models to date.…”

Section: Introductionmentioning

confidence: 99%

Retinal Degeneration In A Mouse Model Of CLN5 Disease Is Associated With Compromised Autophagy

Leinonen

Keksa-Goldsteine

Ragauskas

et al. 2017

Sci Rep

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The Finnish variant of late infantile neuronal ceroid lipofuscinosis (CLN5 disease) belongs to a family of neuronal ceroid lipofuscinosis (NCLs) diseases. Vision loss is among the first clinical signs in childhood forms of NCLs. Mutations in CLN5 underlie CLN5 disease. The aim of this study was to characterize how the lack of normal functionality of the CLN5 protein affects the mouse retina. Scotopic electroretinography (ERG) showed a diminished c-wave amplitude in the CLN5 deficient mice already at 1 month of age, indicative of pathological events in the retinal pigmented epithelium. A- and b-waves showed progressive impairment later from 2 and 3 months of age onwards, respectively. Structural and immunohistochemical (IHC) analyses showed preferential damage of photoreceptors, accumulation of autofluorescent storage material, apoptosis of photoreceptors, and strong inflammation in the CLN5 deficient mice retinas. Increased levels of autophagy-associated proteins Beclin-1 and P62, and increased LC3b-II/LC3b-I ratio, were detected by Western blotting from whole retinal extracts. Photopic ERG, visual evoked potentials, IHC and cell counting indicated relatively long surviving cone photoreceptors compared to rods. In conclusion, CLN5 deficient mice develop early vision loss that reflects the condition reported in clinical childhood forms of NCLs. The vision loss in CLN5 deficient mice is primarily caused by photoreceptor degeneration.

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“…To date, murine models have been identified for CLN1 (14)(15)(16)(17), CLN2 (18), CLN3 (17,(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), CLN5 (29), CLN6 (30), CLN8 (31)(32)(33)(34)(35), and CLN10 (36,37). Reports of retinopathy characterization in murine models of NCL predominantly describe findings in CLN3 (19,28), CNL5 (38), CNL6 (39), and CLN8 (32)(33)(34)(35), though the available descriptions of ocular disease associated with CLN8 are limited to homozygous motor neuron degeneration (mnd) murine models. Neural degeneration in the mnd model results from spontaneous defect in the murine orthologue of CLN8 and exhibits pathology similar to human NCLs (32,40).…”

Section: Introductionmentioning

confidence: 99%

“…Spontaneous mutations in CLN8 have also been identified in canines (41)(42)(43) To the authors' knowledge, phenotypic characterization of retinopathy in CLN8 murine models is limited to a report of indirect ophthalmoscopic and electroretinographic findings, and limited reports of histopathological changes in mnd mice (33)(34)(35)40). The aim of this study was therefore to define the clinical, electrophysiologic, and anatomic retinal changes in a novel mouse model with targeted deletion of Cln8.…”

Section: Introductionmentioning

confidence: 99%

Retinal degeneration in mice and humans with neuronal ceroid lipofuscinosis type 8

Salpeter¹,

Leonard²,

Lopez³

et al. 2021

Ann Transl Med

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Background: Ceroid 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.Methods: Cln8 −/− 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.Results: Retinal 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

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Progression of early postnatal retinal pathology in a mouse model of neuronal ceroid lipofuscinosis

Cited by 19 publications

References 24 publications

Sustained Neural Stem Cell-Based Intraocular Delivery of CNTF Attenuates Photoreceptor Loss in the nclf Mouse Model of Neuronal Ceroid Lipofuscinosis

Sustained Neural Stem Cell-Based Intraocular Delivery of CNTF Attenuates Photoreceptor Loss in the nclf Mouse Model of Neuronal Ceroid Lipofuscinosis

Retinal Degeneration In A Mouse Model Of CLN5 Disease Is Associated With Compromised Autophagy

Retinal degeneration in mice and humans with neuronal ceroid lipofuscinosis type 8

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