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  • 1
    Publication Date: 2013-09-08
    Description: Sandhoff disease (SD) is a lysosomal storage disorder caused by a lack of a functional β-subunit of the β-hexosaminidase A and B enzymes, leading to the accumulation of gangliosides in the central nervous system (CNS). The Hexb –/– mouse model of SD shows a progressive neurodegenerative phenotype similar to the human equivalent. Previous studies have revealed that Hexb –/– mice suffer from chronic neuroinflammation characterized by microglial activation and expansion. Tumor necrosis factor-α (TNFα), a key modulator of the CNS immune response in models of neurodegeneration, is a hallmark of this activation. In this study, we explore the role of TNFα in the development and progression of SD in mice, by creating a Hexb –/– Tnfα –/– double-knockout mouse. Our results revealed that the double-knockout mice have an ameliorated disease course, with an extended lifespan, enhanced sensorimotor coordination and improved neurological function. TNFα-deficient SD mice also show decreased levels of astrogliosis and reduced neuronal cell death, with no alterations in neuronal storage of gangliosides. Interestingly, temporal microglia activation appears similar between the Hexb –/– Tnfα –/– and SD mice. Evidence is provided for the TNFα activation of the JAK2/STAT3 pathway as a mechanism for astrocyte activation in the disease. Bone marrow transplantation experiments reveal that both CNS-derived and bone marrow-derived TNFα have a pathological effect in SD mouse models, with CNS-derived TNFα playing a larger role. This study reveals TNFα as a neurodegenerative cytokine mediating astrogliosis and neuronal cell death in SD and points to TNFα as a potential therapeutic target to attenuate neuropathogenesis.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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    Publication Date: 1994-12-15
    Print ISSN: 1059-910X
    Electronic ISSN: 1097-0029
    Topics: Natural Sciences in General
    Published by Wiley
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  • 5
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Microscopy Research and Technique 29 (1994), S. 468-480 
    ISSN: 1059-910X
    Keywords: Endosomes ; Lysosomes ; Sertoli cells ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Natural Sciences in General
    Notes: The epithelial nonciliated cells of the efferent ducts are specialized in internalizing many luminal substances. The nonciliated cells actively endocytose sulfated glycoprotein-2 (SGP-2), a major secretory protein of Sertoli cells and a homologue of human apolipoprotein J. This study was undertaken to investigate the internalization of Sertoli-derived SGP-2 and synthesis of an endogenous efferent duct form of SGP-2 by nonciliated cells targeted to their secondary lysosomes on animals whose efferent ducts were ligated and/or received injections of tunicamycin. The regulation of synthesis of the endogenous form of SGP-2 within nonciliated cells by hormones in general and testosterone in particular was also examined using hypophysectomized and castrated animals with or without subsequent testosterone replacement. Quantitative electron microscope immunocytochemistry was performed on groups of animals fixed with 4% paraformaldehyde and 0.5% glutaraldehyde in phosphate buffer for each experimental condition and their controls. In each case, the labeling density (number of gold particles/μm2) within the endosomal (endosomes) and lysosomal (dense multivesicular bodies and secondary lysosomes) compartments was calculated. The results revealed that ligation of the efferent ducts resulted in a significant decrease in the labeling density of the endosomal and lysosomal compartments. However, a baseline of about 18% of controls was still observed in the lysosomal compartment 24 h after ligation. In this compartment similar values were noted 24 h after tunicamycin treatment in conjaction with or without ligation. These results suggest that an endogenous form of SGP-2 is synthesized by nonciliated cells and presumably targeted via small vesicles from the Golgi apparatus to the lysosomal compartment, but that the major portion of SGP-2 within this compartment is derived via endocytosis of testicular SGP-2. Hypophysectomy and castration also showed significant decreases in the labeling densities of these two compartments, but again a baseline level of labeling was noted in the lysosomal compartment. Subsequent testosterone administration to 7-day hypophysectomized or castrated animals had no effect on the labeling density of the lysosomal compartment, as values comparable to the effect of hypophysectomy or castration alone were noted. Taken together these results suggest that the nonciliated cells of the efferent ducts synthesize an endogenous form of SGP-2 that is targeted to the lysosomal compartment and which is not regulated by pituitary factors or testosterone. © 1994 Wiley-Liss, Inc.
    Additional Material: 15 Ill.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Molecular Reproduction and Development 40 (1995), S. 69-83 
    ISSN: 1040-452X
    Keywords: SGP-1 ; Hypophysectomy ; Castration ; Efferent ducts ; Lysosomes ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology
    Notes: The objective of this study was to define the factors regulating the endogenous production of sulfated glycoprotein-1 (SGP-1) in nonciliated cells of the efferent ducts. To this end we examined five different groups of animals undergoing the following experimental procedures: (1) hypophysectomized animals at 7, 14, and 28 days, (2) 7-day hypophysectomized rats receiving testosterone implants given at various time intervals thereafter, (3) castration at various time intervals up to 7 days, (4) 7-day castrated rats receiving testosterone implants at various time intervals thereafter, and (5) castrated rats given testosterone implants immediately after castration and sacrificed at different time intervals thereafter. Efferent ducts were fixed by perfusion with 4% paraformaldehyde and 0.5% glutaraldehyde in phosphate buffer for quantitative immunocytochemical analysis at the level of the electron microscope. For each experimental condition and their controls, the number of gold particles/μm2 within the endosomal and lysosomal compartments was calculated taking into account the changes in both the volume of the cell and organelles being quantified and expressed as labeling content. The results revealed that hypophysectomy (up to 4 weeks) caused a marked significant decrease in the SGP-1 labeling content of the endosomal and lysosomal compartments. The labeling content of the lysosomal compartment of efferent ducts from rats castrated for up to 1 week did not change significantly. However, there was a significant decrease in the labeling content of endosomes. This decrease is due to SGP-1, which is secreted by Sertoli cells, not being available for uptake in the efferent aucts. These results suggested that testosterone is not required for maintaining the high labeling content of SGP-1 within lysosomes of nonciliated cells, but that a pituitary factor appears to be needed. The administration of testosterone at different intervals to 7-day castrated animals resulted in a significant decrease of lysosomal SGP-1, suggesting that testosterone under these experimental conditions inhibits the production of a pituitary factor that maintains the high labeling content of SGP-1 within lysosomes of the nonciliated cells. Testosterone administered to 7-day hypophysectomized animals over a 24-hr period had no effect on the labeling content of SGP-1 within lysosomes. However, the administration of testosterone to animals immediately following castration showed no differences in the labeling content of SGP-1 within compared to controls. Together these results suggest that the labeling content of SGP-1 within lysosomes of nonciliated cells of the efferent ducts is not dependent on luminal or circulating androgens, nor is it dependent on a testicular factor entering the lumen of the ducts. It does appear, however, that SGP-1 synthesis and targeting to secondary lysosomes is dependent on a pituitary factor that may have a direct or an indirect effect on the nonciliated cells. © 1995 Wiley-Liss, Inc.
    Additional Material: 13 Ill.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Molecular Reproduction and Development 41 (1995), S. 287-299 
    ISSN: 1040-452X
    Keywords: SGP-1 ; SGP-2 ; Postnatal development ; Nonciliated cells ; Efferent ducts ; Rats ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology
    Notes: Sulfated glycoprotein (SGP) -1 and -2, secretory products of Sertoli cells, are secreted into the lumen of seminiferous tubules where they bind to late spermatids. Once released, the spermatozoa traverse the efferent ducts where these proteins detach from their surface and are endocytosed by the nonciliated cells. In adult animals, SGP-1 and SGP-2 are also synthesized by nonciliated cells and targeted from the Golgi apparatus to lysosomes. The purpose of the present study was to determine the pattern of expression of SGP-1 and SGP-2 within nonciliated cells during postnatal development. The efferent ducts of animals at different postnatal ages were prepared for an electron microscopic immunocytochemical quantitative analysis as well as for Northern blot analysis. The data expressed as labeling content (no. gold particles/μm2 and taking into account the volume of the endocytic or-ganelles and the cell) revealed that anti-SGP-1 labeling in endosomes of nonciliated cells was minimal at 15, 21, and 29 days of age. On the other hand, the lysosomal labeling content showed a significant increase by day 29 compared to 15 and 21-day-old animals indicating that an endogenous form of SGP-1 was being synthesized by nonciliated cells and targeted to lysosomes. By day 39 a significant increase in endosomal labeling occurred; this was attributed to the endocytosis of Sertoli-derived SGP-1 which coincided with the entry of spermatozoa into the lumen of these ducts at this age. Lysosomal labeling showed further significant increases at days 39, 49, and then again at day 90. Northern blot analysis detected SGP-1 mRNA transcripts at all postnatal ages examined. While decreases or increases in transcripts could not be determined due to the greater amount of tissue present with increasing age, these data taken together support the idea of an endogenous form of SGP-1 being synthesized by nonciliated cells and targeted to lysosomes during postnatal development.In the case of SGP-2, endosomal labeling was minimal at 15, 21, and 29 days of age but was significantly increased by day 39, with similar values at all subsequent ages. The high value at day 39 was attributed to the endocytosis of SGP-2 which coincided with the entry of spermatozoa into the lumen at this age. Lysosomal labeling, on the other hand, was low at days 15 and 21 but peaked at day 29 at a time when endosomal labeling was minimal. These results suggested the synthesis of an endogenous form of SGP-2 which was being targeted to lysosomes. Similar values for SGP-2 lysosomal labeling comparable to that at day 29 were obtained at all other ages. Since SGP-2 endosomal labeling was significantly increased at day 39 and maintained thereafter, it is suggested that labeling in lysosomes at this and subsequent ages could also be due to the endocytosis of Sertoli-derived SGP-2. However, Northern blot analysis confirmed the presence of mRNA transcripts for SGP-2 at all postnatal ages examined, although increases or decreases in their amount were not determined. These results thus consolidate the hypothesis of an endogenous form of SGP-2 being synthesized by nonciliated cells and targeted to lysosomes. Finally, since the amounts of endogenous SGP-1 and SGP-2 peak at different ages, it is suggested that different factors are involved in regulation of these two proteins during postnatal development. © 1995 Wiley-Liss, Inc.
    Additional Material: 12 Ill.
    Type of Medium: Electronic Resource
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