Defects in the retina of Niemann-pick type C 1 mutant mice

Yan, Xin; Ma, Lucy; Hovakimyan, Marina; Lukáš, Jan; Wree, Andreas; Frank, Marcus; Guthoff, Rudolf; Rolfs, Arndt; Witt, Martin; Luo, Jiankai

doi:10.1186/s12868-014-0126-2

Cited by 18 publications

(19 citation statements)

References 46 publications

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“…In GD ganglion cell layer atrophy was found in GD patients but also in asymptomatic mutation carriers [17]. Indeed, animal studies in NPC1-mutant mice demonstrated preclinical retinal degeneration and lipofuscin accumulation in the pigment epithelium and ganglion cells, electrodense inclusions in various cell types, photoreceptor defects, and hyperactivity of glial cells [42,46], as well as optic nerve pallor and per macular grey discoloration [47]. Given the pathomechanistic similarities between NPC and GD, we encourage additional work in NPC heterozygotes to shed further light on potential similar risks.…”

Section: Discussionmentioning

confidence: 99%

Retinal axonal degeneration in Niemann–Pick type C disease

et al. 2020

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Objective Niemann-Pick disease type C1 (NPC1) is a rare autosomal-recessive lysosomal storage disorder presenting with a broad clinical spectrum ranging from a severe infantile-onset neurovisceral disorder to late-onset neurodegenerative disease. Optical coherence tomography (OCT) is established to detect retinal degeneration in vivo. We examined NPC1-patients (NPC1-P), clinically asymptomatic NPC1-mutation carriers (NPC1-MC), and healthy controls (HC) to (1) identify retinal degeneration in NPC1-disease and (2) to investigate possible subclinical retinal degeneration in NPC1-MC. Methods Fourteen NPC1-P, 17 NPC1-MC, and 31 age-matched HC were examined using spectral-domain OCT. Neurological examinations, clinical scales [modified Disability Rating Scale (mDRS); Scale for the Rating and Assessment of Ataxia (SARA); Spinocerebellar Ataxia Functional Index (SCAFI)], and video-oculography (VOG) were correlated with OCT data. Results Macular retinal nerve fiber layer and volumes of combined ganglion cell and inner plexiform layer were significantly lower in NPC1-P compared to HC [mRNFL (µm):0.13 ± 0.01 vs. 0.14 ± 0.02; p = 0.01; GCIPL (mm 3):0.60 ± 0.05 vs. 0.62 ± 0.04; p = 0.04]. No significant differences were found in NPC1-MC in comparison to HC. In NPC1-P, the amplitude of upward vertical saccades showed positive associations with peripapillary RNFL (ρ = 0.645; p < 0.05), and thinned GCIP (ρ = 0.609; p < 0.05), but not in NPC1-MC. In NPC1-P correlations between combined outer plexiform layer and outer nuclear layer (OPONL) with mDRS (r = − 0.617; p < 0.05) and GCIP with SARA (r = − 0.622; p < 0.05) were observed. Furthermore, in NPC1-MC, motor scores were negatively associated with pRNFL (ρ = − 0.677; p < 0.01). Conclusions Using OCT, we showed retinal degeneration in NPC1-P and significant correlation between retinal neuroaxonal degeneration with clinical measurements. We observed a non-significant trend of retinal degeneration in NPC1-MC correlating with subclinical motor abnormalities. Based on these preliminary data, OCT may be an important marker of neurodegeneration in NPC1-disease after onset of clinical symptoms.

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Section: Discussionmentioning

confidence: 99%

Retinal axonal degeneration in Niemann–Pick type C disease

et al. 2020

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“…These abnormalities are likely associated with an impairment of various sensory pathways, as already indicated by the deficit of auditory [ 11 , 49 ] and olfactory [ 50 ] systems in Npc1 −/− mice and of multisensory processing in NPC patients [ 51 ]. As for the visual system of Npc1 −/− mice, retinal cellular and functional defects were recently described [ 19 , 20 ], but the functional integrity of their visual pathway has not been investigated yet. Now addressing this issue, we report that the transmission of visual stimuli from retina to visual cortex is strongly influenced by the lack of Npc1 function.…”

Section: Discussionmentioning

confidence: 99%

“…Besides the auditory pathway, the cellular dysfunctions of Npc1 −/− mouse retina and dLGN suggest that the visual pathway is also affected in NPC1 disease. Morphological and functional anomalies of the retina of these mice were recently reported, showing age-related degeneration of photoreceptors and a number of anomalies in several cell types of the visual system, including increased autophagy in retinal ganglion cell layer (GCL), electron-dense inclusions in bipolar and Müller cells, abnormal arborization of horizontal and amacrine cells, altered myelination, dilated axons of the optic nerve [ 19 ] and reduced amplitude of electroretinogram (ERG) responses [ 20 ]. However, studies investigating the functional integrity of the visual pathway from retina to visual cortex are still lacking.…”

Section: Introductionmentioning

confidence: 99%

Visual evoked potentials of Niemann-Pick type C1 mice reveal an impairment of the visual pathway that is rescued by 2-hydroxypropyl-ß-cyclodextrin

Palladino

Loizzo

Fortuna

et al. 2015

Orphanet J Rare Dis

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BackgroundThe lysosomal storage disorder, Niemann Pick type C1 (NPC1), presents a variable phenotype including neurovisceral and neurological symptoms. 2-Hydroxypropyl-ß-cyclodextrin (HPßCD)-based therapies are presently the most promising route of intervention. While severe cerebellar dysfunction remains the main disabling feature of NPC1, sensory functions including auditory and olfactory ones are also affected. Morphological and functional anomalies of Npc1−/− mouse retina have also been observed, although the functional integrity of the visual pathway from retina to visual cortex is still unsettled. We have addressed this issue by characterizing the visual evoked potential (VEP) response of Npc1−/− mice and determining if/how HPßCD administration influences the VEPs of both Npc1−/− and Npc1+/+ mice.MethodsVEP elicited by a brief visual stimulus were recorded from the scalp overlying the visual cortex of adult (PN, postnatal days 60, 75, 85 and 100) Npc1+/+ and Npc1−/− mice that had received repeated injections of either HPßCD or plain vehicle. The first injection was given at PN4 and was followed by a second one at PN7 and thereafter by weekly injections up to PN49. Cholesterol accumulation and myelin loss were finally assessed by filipin staining and myelin basic protein immunohistochemistry, respectively.Results and discussionWe have found that the transmission of visual signals from retina to visual cortex is negatively influenced by the loss of Npc1 function. In fact, the VEP response of Npc1−/− mice displayed a highly significant increase in the latency compared to that of Npc1+/+ mice. HPßCD administration fully rescued this defect and counteracted the cholesterol accumulation in retinal ganglion cells and dorsal lateral geniculate nucleus neurons, as well as the myelin loss in optic nerve fibers and axons projecting to the visual cortex observed in of Npc1−/− mice. By contrast, HPßCD administration had no effect on the VEP response of Npc1+/+ mice, further strengthening the treatment efficacy.ConclusionsThis study pinpoints the analysis of VEP response as a potentially accurate and non-invasive approach to assess neural activity and visual information processing in NPC1 patients, as well as for monitoring the progression of the disease and assessing the efficacy of potential therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0348-0) contains supplementary material, which is available to authorized users.

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“…Then, cardiac perfusion with phosphate-buffered saline (PBS, pH = 7.4) was followed by 4% paraformaldehyde (PFA) in 0.1 M PBS. As previously described by our group [ 50 ] after perfusion and preparation liver samples were excised and postfixed in 0.1 M phosphate buffer containing 2.5% glutaraldehyde for at least 24 h at 4 °C. Thereafter, the specimens were osmicated, washed, block contrasted with 2% aqueous uranyl acetate, dehydrated through a graded series of ethanol, and embedded in Epon 812 (Plano GmbH, Marburg, Germany).…”

Section: Methodsmentioning

confidence: 99%

Evaluation of Two Liver Treatment Strategies in a Mouse Model of Niemann–Pick-Disease Type C1

Ebner

Gläser

Bräuer

et al. 2018

IJMS

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Niemann–Pick-disease type C1 (NPC1) is an autosomal-recessive cholesterol-storage disorder. Besides other symptoms, NPC1 patients develop liver dysfunction and hepatosplenomegaly. The mechanisms of hepatomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood. Here, we used an NPC1 mouse model to study an additive hepatoprotective effect of a combination of 2-hydroxypropyl-β-cyclodextrin (HPβCD), miglustat and allopregnanolone (combination therapy) with the previously established monotherapy using HPβCD. We examined transgene effects as well as treatment effects on liver morphology and hepatic lipid metabolism, focusing on hepatic cholesterol transporter genes. Livers of Npc1−/− mice showed hepatic cholesterol sequestration with consecutive liver injury, an increase of lipogenetic gene expression, e.g., HMG-CoA, a decrease of lipolytic gene expression, e.g., pparα and acox1, and a decrease of lipid transporter gene expression, e.g., acat1, abca1 and fatp2. Both, combination therapy and monotherapy, led to a reduction of hepatic lipids and an amelioration of NPC1 liver disease symptoms. Monotherapy effects were related to pparα- and acox1-associated lipolysis/β-oxidation and to fatp2-induced fatty acid transport, whereas the combination therapy additionally increased the cholesterol transport via abca1 and apoE. However, HPβCD monotherapy additionally increased cholesterol synthesis as indicated by a marked increase of the HMG-CoA and srebp-2 mRNA expression, probably as a result of increased hepatocellular proliferation.

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Defects in the retina of Niemann-pick type C 1 mutant mice

Cited by 18 publications

References 46 publications

Retinal axonal degeneration in Niemann–Pick type C disease

Retinal axonal degeneration in Niemann–Pick type C disease

Visual evoked potentials of Niemann-Pick type C1 mice reveal an impairment of the visual pathway that is rescued by 2-hydroxypropyl-ß-cyclodextrin

Evaluation of Two Liver Treatment Strategies in a Mouse Model of Niemann–Pick-Disease Type C1

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