Involvement of Retinal Neurons and Pigment Epithelial Cells in a Murine Model of Sandhoff Disease

Sango, Kazunori; Yamanaka, Shōji; Ajiki, Kyoko; Arai, Nobutaka; Takano, Masahiko

doi:10.1159/000127831

Cited by 11 publications

(6 citation statements)

References 53 publications

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“…The function of CERKL is not yet known but is potentially involved in the Cer metabolic pathway, suggesting a direct link between human retinal degeneration and Cer-mediated apoptosis. Additionally, in several inherited sphingolipid metabolism defect diseases commonly known as ‘lipid storage disease’, such as Krabbe’s disease (Brownstein et al 1978), Niemann-Pick disease (Robb and Kuwabara 1973), Sandhoff disease (Sango et al 2008), and Gaucher disease (Seidova et al 2009), retinal impairment and vision loss due to retinal neuronal cell death are often present and accompanied by Cer accumulation. Increased level of Cer was found in retinas of patients with Farber disease, caused by a mutation in Ceramidase gene (also known as ceramidase deficiency) (Zarbin et al 1985; Zarbin et al 1988).…”

Section: 3 Ceramide In Photoreceptor Apoptosismentioning

confidence: 99%

Ceramide Signaling in Retinal Degeneration

Chen

Tran

Brush

et al. 2011

Advances in Experimental Medicine and Biology

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Retinal degenerations (RD) are a complex heterogeneous group of diseases in which retinal photoreceptors and the supporting retinal pigment epithelial cells die irreversibly, causing visual loss for millions of people. Mutations on more than 150 genes have been discovered for RD and there are many forms that possess complex etiology involving more than one gene and environmental effect. For years many have searched for some common intracellular second messenger for these many forms of cell death which could be targeted for therapy. Ceramide is a novel cellular second messenger which signals for apoptosis. Several lines of evidence suggest an integral role of ceramide in photoreceptor apoptosis and cell death. Understanding their role in the pathogenic pathways of retinal degenerative diseases is important for development of targeted therapeutics.

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Section: 3 Ceramide In Photoreceptor Apoptosismentioning

confidence: 99%

Ceramide Signaling in Retinal Degeneration

Chen

Tran

Brush

et al. 2011

Advances in Experimental Medicine and Biology

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“…Due to its chemical structure that allows for tight packing, Cer regulates membrane properties, enzymes responsible for their degradation, occurs in several inherited diseases, and is often associated with retinal impairment and vision loss due to retina neuronal cell death (8)(9)(10)(11); however, the mechanisms leading to this death are uncertain. In this review, we will focus on the socalled "simple sphingolipids" Cer, Sph, and S1P, as opposed to sphingolipids with more complex headgroups ( 12 ).…”

Section: Cer a Deadly Second Messengermentioning

confidence: 99%

Regulating survival and development in the retina: key roles for simple sphingolipids

Rotstein

Miranda

Abrahan

et al. 2010

Journal of Lipid Research

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tions as structural membrane components and energetic fuels. However, the fi ndings of the previous half century have extended these roles, shedding light on their indisputable relevance as signaling molecules controlling key aspects of cellular life and development. The identifi cation of diacylglycerol and inositol 1,4,5 triphosphate ( 1 ) as second messengers seemed at the time a peculiarity of these lipids. The subsequent fi ndings of the roles of arachidonic acid metabolites ( 2 ), platelet activating factor ( 3 ), and other minor inositol lipids ( 4 ) in cell signaling began to establish that being intracellular messengers was not an oddity but a habitual task for lipids in cells. The family of lipid signaling molecules largely expanded in the last two decades, when several sphingolipids were successively shown to regulate a multiplicity of cell functions. Sphingosine (Sph) was the fi rst sphingolipid to be established as a bioactive lipid, involved in the regulation of protein kinase (PK)C activity ( 5 ). Ceramide (Cer) and sphingosine-1-phosphate (S1P) were next shown to signal a myriad of cell functions and the number of sphingolipid molecules with bioactive properties has gone on enlarging in recent years ( 6, 7 ).Though a vast literature exists on the functions of sphingolipids in several tissues, less is known concerning its roles in the eye, and in the retina in particular. Accumulation of sphingolipids originated in defects in the lysosomal Abstract Many sphingolipids have key functions in the regulation of crucial cellular processes. Ceramide (Cer) and sphingosine (Sph) induce growth arrest and cell death in multiple situations of cellular stress. On the contrary, sphingosine-1-phosphate (S1P), the product of Sph phosphorylation, promotes proliferation, differentiation, and survival in different cell systems. This review summarizes the roles of these simple sphingolipids in different tissues and then analyzes their possible functions in the retina. Alterations in proliferation, neovascularization, differentiation, and cell death are critical in major retina diseases and collective evidence points to a role for sphingolipids in these processes. Cer induces infl ammation and apoptosis in endothelial and retinal pigmented epithelium cells, leading to several retinopathies. S1P can prevent this death but also promotes cell proliferation that might lead to neovascularization and fibrosis. Recent data support Cer and Sph as crucial mediators in the induction of photoreceptor apoptosis in diverse models of oxidative damage and neurodegeneration, and suggest that regulating their metabolism can prevent this death. New evidence proposes a central role for S1P controlling photoreceptor survival and differentiation. Finally, this review discusses the ability of trophic factors to regulate sphingolipid metabolism and transactivate S1P signaling pathways to control survival and development in retina photoreceptors. When asked about the roles of cellular lipids, the fi rst thought usually coming to our minds re...

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“…Additionally, studies have provided evidence that misregulation of SPL metabolism can lead to retinal degeneration (review [ 10 , 11 ]). Importantly, some lipid storage diseases, which are caused by disorders of sphingolipid metabolism, such as Krabbe’s disease [ 12 ], and Sandhoff disease [ 13 ], are characterized by vision loss. Although current evidence suggests a strong connection between SPL metabolism and retinopathy, the exact roles of these lipids in the retina are mostly unknown.…”

Section: Introductionmentioning

confidence: 99%

Lack of Acid Sphingomyelinase Induces Age-Related Retinal Degeneration

Fan

Boyer

et al. 2015

PLoS ONE

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BackgroundMutations of acid sphingomyelinase (ASMase) cause Niemann–Pick diseases type A and B, which are fatal inherited lipid lysosomal storage diseases, characterized with visceral organ abnormalities and neurodegeneration. However, the effects of suppressing retinal ASMase expression are not understood. The goal of this study was to determine if the disruption of ASMase expression impacts the retinal structure and function in the mouse, and begin to investigate the mechanisms underlying these abnormalities.MethodsAcid sphingomyelinase knockout (ASMase KO) mice were utilized to study the roles of this sphingolipid metabolizing enzyme in the retina. Electroretinogram and morphometric analysis were used to assess the retinal function and structure at various ages. Sphingolipid profile was determined by liquid chromatography-mass spectrometry. Western blots evaluated the level of the autophagy marker LC3-II.ResultsWhen compared to control animals, ASMase KO mice exhibited significant age-dependent reduction in ERG a- and b-wave amplitudes. Associated with these functional deficits, morphometric analysis revealed progressive thinning of retinal layers; however, the most prominent degeneration was observed in the photoreceptor and outer nuclear layer. Additional analyses of ASMase KO mice revealed early reduction in ERG c-wave amplitudes and increased lipofuscin accumulation in the retinal pigment epithelium (RPE). Sphingolipid analyses showed abnormal accumulation of sphingomyelin and sphingosine in ASMase KO retinas. Western blot analyses showed a higher level of the autophagosome marker LC3-II.ConclusionsThese studies demonstrate that ASMase is necessary for the maintenance of normal retinal structure and function. The early outer retinal dysfunction, outer segment degeneration, accumulation of lipofuscin and autophagosome markers provide evidence that disruption of lysosomal function contributes to the age-dependent retinal degeneration exhibited by ASMase KO mice.

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Involvement of Retinal Neurons and Pigment Epithelial Cells in a Murine Model of Sandhoff Disease

Cited by 11 publications

References 53 publications

Ceramide Signaling in Retinal Degeneration

Ceramide Signaling in Retinal Degeneration

Regulating survival and development in the retina: key roles for simple sphingolipids

Lack of Acid Sphingomyelinase Induces Age-Related Retinal Degeneration

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