Neurochemical, morphological, and neurophysiological abnormalities in retinas of Sandhoff and GM1 gangliosidosis mice

Denny, Christine A.; Alroy, Joseph; Pawlyk, Basil; Sandberg, Michael A.; d’Azzo, Alessandra; Seyfried, Thomas N.

doi:10.1111/j.1471-4159.2007.04525.x

Cited by 21 publications

(29 citation statements)

References 35 publications

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“…4C) indicative of increased "anxiety-like" behavior in the hexb−/−mice. We have employed a behavioral test battery to assess a mouse model of Sandhoff disease that we backbred onto the C57BL/6J background.We demonstrated deficits in motor activity, and coordination consistent with those previously reported [1,7,8,13,14,16,18,20,22,25,27,28] suggesting no significant effect of genetic background. However, we were also able to detect deficits as early as 66 days using the balance beam test.…”

supporting

confidence: 91%

“…Previous electrophysiological studies of visual function in Sandhoff mice have been reported in older mice (3.5-4 months). Electroretinograms were normal even at this late stage while visual evoked potentials were generally present [7]. These data, in combination with the normal levels of novel object exploration in Trial 1, normal pupil dilation and normal visual placing in the FOB suggest that deficits in visual function are not sufficient to explain the poor performance in the memory tests.…”

mentioning

confidence: 77%

“…The Sandhoff models have engendered much research directed at overcoming the challenges [1,2,4,11,14,15,18,20]. The knockout model [25] presented here displays ataxia, tremor, muscle wasting, and deficits in motor reflex, coordination and balance [1,4,7,8,13,14,16,18,20,22,25,27,28]. However, systematic studies examining cognitive or affective outcomes are lacking [25].…”

Section: Introductionmentioning

confidence: 99%

“…Both latency (time to cross the beam from end to end) and number of slips (each time a paw fell under the beam midline) were assessed as measures of motor coordination. In the rotarod test, latency to fall from a rotating rod (acceleration increased by 0.5 cm/s every 5 s) was scored automatically with infrared sensors in a Rotamex 5 rotarod (Columbus Inst, Ohio) with four trials per day over 2 days.Behavioral tests were primarily conducted on mice of 79(±2) days old, an age that in most previous assays showed no deficits, but were also performed on some at 66(± 2) and 97(± 2) days when had been typically reported as normal or displaying deficits, respectively [1,4,7,8,13,14,16,18,20,22,25,27,28]. All data are shown as mean ± S.E.M.…”

mentioning

confidence: 99%

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Early deficits in motor coordination and cognitive dysfunction in a mouse model of the neurodegenerative lysosomal storage disorder, Sandhoff disease

Gulinello

Chen

Dobrenis

2008

Behavioural Brain Research

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Mouse models of lysosomal storage diseases, including Sandhoff disease, are frequently employed to test therapies directed at the central nervous system. We backbred such mice and conducted a behavioral test battery which included sensorimotor and cognitive assessments. This is the first report of short-term memory deficits in a murine model of Sandhoff disease. We also document early onset of motor deficits using the balance beam test. KeywordsSandhoff disease; Mouse model; Novel object recognition test; Rotarod; Motor coordination; Balance beam; Open field; Memory Lysosomal storage disorders (LSDs) are a family of inherited diseases with multi-organ involvement frequently including the nervous system. The G M2 gangliosidoses, one class of human LSDs that include Tay-Sachs and Sandhoff diseases, are marked by the lysosomal accumulation of G M2 ganglioside (GM2) in neurons throughout the nervous system. Sandhoff disease arises from defects in the gene encoding the β-subunit (hexb) of β-Nacetyl-d-hexosaminide N-acetylhexosaminohydrolase (EC 3.2.1.52) normally involved in the sequential catabolism of gangliosides and other glycoconjugates [11]. Sandhoff patients have widespread brain pathology which results in clinical symptoms including progressive mental and motor deterioration [10,11,21].Two transgenic murine models of Sandhoff disease exist [23,25] that, like the human equivalent, exhibit premature death and display widespread neuronal storage of ganglioside, in addition to gliotic and inflammatory reactions and neuronal cell death [11,16,23,25,27]. The Sandhoff models have engendered much research directed at overcoming the challenges [1,2,4,11,14,15,18,20]. The knockout model [25] presented here displays ataxia, tremor, muscle wasting, and deficits in motor reflex, coordination and balance [1,4,7,8,13,14,16,18,20,22,25,27,28]. However, systematic studies examining cognitive or affective outcomes are lacking [25]. Clearly, these latter studies would be valuable to evaluate CNS-specific improvements, and would be most meaningful if assays pertinent to human neurologic assessments were employed to facilitate transition to clinical trials. Furthermore, the Sandhoff mice rarely show overt clinical signs before 3 months old and then rapidly decline, typically becoming moribund between 4 and 5 months of age [1,[13][14][15]18,20,22,25,27,28]. Therefore, behavioral assays should ideally be able to identify cognitive deficits in subjects that have multiple behavioral outcomes. In addition, increased assay sensitivity could permit behavioral assessment at earlier ages thereby also providing better evaluation of therapeutic strategies which seek earlier intervention.We Heterozygous breeders of the B6; 129S4-Hexβ tm1R1p strain [25] (Jackson Labs, Maine) were backbred through 10 generations by mating with C57BL/6J mice. Then the backbred heterozygotes were mated together and progeny genotyped using a standardized PCR protocol (provided by Jackson Labs) on tail-tip DNA extracts. Studies were performed using homozy...

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supporting

confidence: 91%

mentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Early deficits in motor coordination and cognitive dysfunction in a mouse model of the neurodegenerative lysosomal storage disorder, Sandhoff disease

Gulinello

Chen

Dobrenis

2008

Behavioural Brain Research

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“…Indeed, GG composition of the retina undergoes drastic changes during the development of the tissue, concomitantly to morphologic differentiation ( 15 ). Mouse models of GM2 gangliosidosis exhibit retinal abnormalities with visual defi ciency ( 16,17 ). Moreover, GM1 injections into the vitreous can protect the retina from lesions induced by ischemia ( 18 ) or optic nerve axotomy ( 19 ).…”

Section: Extraction Separation and Purifi Cation Of Ggsmentioning

confidence: 99%

Apprehending ganglioside diversity: a comprehensive methodological approach

Masson

Sibille

Martine

et al. 2015

Journal of Lipid Research

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Gangliosides make a wide family of glycosphingolipids ubiquitously expressed in mammalian tissues and particularly abundant in the brain and nervous system. They exhibit a huge diversity due to structural variations in both their oligosaccharidic chain and ceramide moiety, which represent a real analytical challenge. Since their discovery in the 1940s, methods have persistently improved until the emergence of Liquid Chromatography/Mass Spectrometry (LC/MS) which offers a high level of specificity and sensitivity and is suitable with high-throughput profiling studies. We describe here a comprehensive approach relying on various techniques and aiming at fully characterizing gangliosides in biological samples. First, total ganglioside content was determined by a biochemical assay. Second, ganglioside class composition was assessed by high performance thin layer chromatography followed by colorimetric revelation. Then, ceramide types of ganglioside classes were identified and their relative quantification was performed thanks to the development of a powerful and reliable LC/MS method. Finally, ceramides were structurally characterized and minor and less common ganglioside classes were identified using high resolution MS. These methods were applied to the rat retina to provide an exhaustive description of its ganglioside composition, giving the base for a better understanding of the precise roles of gangliosides in this tissue

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Metastatic cancer cells with macrophage properties: Evidence from a new murine tumor model

Huysentruyt

Mukherjee

Banerjee

et al. 2008

Intl Journal of Cancer

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154

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Metastasis is the process by which cancer cells disseminate from the primary neoplasm and invade surrounding tissue and distant organs, and is the primary cause of morbidity and mortality for cancer patients. Most conventional cancer therapies are ineffective in managing tumor metastasis. This has been due in large part to the absence of in vivo metastatic models that represent the full spectrum of metastatic disease. Here we identify 3 new spontaneously arising tumors in the inbred VM mouse strain, which has a relatively high incidence of CNS tumors. Two of the tumors (VM-M2 and VM-M3) reliably expressed all of the major biological processes of metastasis to include local invasion, intravasation, immune system survival, extravasation and secondary tumor formation involving liver, kidney, spleen, lung and brain. Metastasis was assessed through visual organ inspection, histology, immunohistochemistry and bioluminescence imaging. The metastatic VM tumor cells also expressed multiple properties of macrophages including morphological appearance, surface adhesion, phagocytosis, total lipid composition (glycosphingolipids and phospholipids) and gene expression (CD11b, Iba1, F4/80, CD68, CD45 and CXCR4). The third tumor (VM-NM1) grew rapidly and expressed properties of neural stem/progenitor cells, but was neither invasive nor metastatic. Our data indicate that spontaneous brain tumors can arise from different cell types in VM mice and that metastatic cancer can represent a disease of macrophage-like cells similar to those described in several human metastatic cancers.The new VM tumor model will be useful for defining the biological processes of cancer metastasis and for evaluating potential therapies for tumor management. ' 2008 Wiley-Liss, Inc.Key words: metastasis; microglia; gangliosides; neural stem cell; glioblastoma Metastasis is the process by which cancer cells disseminate from the primary neoplasm and invade surrounding tissue and distant organs and is the primary cause of morbidity and mortality for cancer patients. This process involves cancer cell detachment from the primary tumor, intravasation into the circulation, evasion of immune attack, extravasation at distant capillary beds and invasion and proliferation in distant organs. [1][2][3] In addition, the metastatic cells establish a microenvironment facilitating colonization (angiogenesis and further proliferation), resulting in macroscopic malignant secondary tumors.1-4 Metastatic cells preferentially invade those organs (lymph nodes, lung, liver, brain, bone, pleura and peritoneum) that promote tumor cell growth and survival consistent with the ''seed and soil'' hypothesis. 1,5,6 The metastatic and invasive potential of cancer cells is often correlated with abnormalities in phospholipids and in cell-surface glycolipids, which contribute to tumor progression.7-10 Hence, aberrant cellular migration and proliferation characterize the metastatic phenomenon.In this study, we analyzed the morphological, behavioral, biochemical and genetic properties of 3 n...

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Neurochemical, morphological, and neurophysiological abnormalities in retinas of Sandhoff and GM1 gangliosidosis mice

Cited by 21 publications

References 35 publications

Early deficits in motor coordination and cognitive dysfunction in a mouse model of the neurodegenerative lysosomal storage disorder, Sandhoff disease

Early deficits in motor coordination and cognitive dysfunction in a mouse model of the neurodegenerative lysosomal storage disorder, Sandhoff disease

Apprehending ganglioside diversity: a comprehensive methodological approach

Metastatic cancer cells with macrophage properties: Evidence from a new murine tumor model

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