Mice lacking both subunits of lysosomal β–hexosaminidase display gangliosidosis and mucopolysaccharidosis

Sango, Kazunori; McDonald, Michael P.; Crawley, Jacqueline N.; Mack, Michelle; Tifft, Cynthia J.; Skop, Elisa; Starr, Christopher M.; Hoffmann, Alexander; Sandhoff, Konrad; Suzuki, Kinuko; Proia, Richard L.

doi:10.1038/ng1196-348

Cited by 191 publications

(158 citation statements)

References 8 publications

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“…Because muscle weakness is the primary clinical component of IBM, we investigated whether deficits in muscle balance and coordination accompanied the underlying histopathological changes in MCK-␤APP muscle. Mice were evaluated on the accelerating rotarod, a well characterized behavioral task designed to assess motor performance (30,31). At the earlier times (Ͻ10 months of age) we did not detect significant differences in performance between transgenic and nontransgenic mice (Fig.…”

Section: Mck-␤app Micementioning

confidence: 99%

Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle

Sugarman

Yamasaki

Oddo³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

106

118

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Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease. Accumulation of the amyloid-␤ peptide, which is derived from proteolysis of the larger amyloid-␤ precursor protein (␤APP), seems to be an early pathological event in Alzheimer's disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of ␤APP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted ␤APP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (>10 months) transgenic mice exhibit intracellular immunoreactivity to ␤APP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of ␤APP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for ␤APP mismetabolism in human IBM.

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Section: Mck-␤app Micementioning

confidence: 99%

Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle

Sugarman

Yamasaki

Oddo³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

106

118

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“…32) and natural mutant BALB/cNctrNpc1 m1N /J Npc1-deficient mice (a model of Niemann-Pick type C disease; Ref. 33) show defects in their ability to positively select and stimulate type 1 NKT cells (31), the effects of the Nkt2b congenic interval on NKT cell stimulation were studied.…”

Section: Effects Of the Nkt2b Congenic Interval On Glycolipid Presentmentioning

confidence: 99%

Congenic Analysis of the NKT Cell Control Gene Nkt2 Implicates the Peroxisomal Protein Pxmp4

Fletcher

Jordan

Snelgrove

et al. 2008

The Journal of Immunology

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Type 1 NKT cells play a critical role in controlling the strength and character of adaptive and innate immune responses. We have previously reported deficiencies in the numbers and function of NKT cells in the NOD mouse strain, which is a well-validated model of type 1 diabetes and systemic lupus erythematosus. Genetic control of thymic NKT cell numbers was mapped to two linkage regions: Nkt1 on distal chromosome 1 and Nkt2 on chromosome 2. Herein, we report the production and characterization of a NOD.Nkrp1b.Nkt2bb congenic mouse strain, which has increased thymic and peripheral NKT cells, a decreased incidence of type 1 diabetes, and enhanced cytokine responses in vivo and increased proliferative responses in vitro following challenge with α-galactosylceramide. The 19 highly differentially expressed candidate genes within the congenic region identified by microarray expression analyses included Pxmp4. This gene encodes a peroxisome-associated integral membrane protein whose only known binding partner is Pex19, an intracellular chaperone and component of the peroxisomal membrane insertion machinery encoded by a candidate for the NKT cell control gene Nkt1. These findings raise the possibility that peroxisomes play a role in modulating glycolipid availability for CD1d presentation, thereby influencing NKT cell function.

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“…29 The wires were 1 mm in diameter and spaced 1 cm apart. A rectangular area of the screen was taped off to confine the mouse to an 18 ϫ 26 cm section of the screen.…”

Section: Wire Hanging Testmentioning

confidence: 99%

Loss of Hrs in the Central Nervous System Causes Accumulation of Ubiquitinated Proteins and Neurodegeneration

Tamai

Toyoshima

Tanaka

et al. 2008

The American Journal of Pathology

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The endosomal sorting complex required for transport (ESCRT) proteins form multimolecular complexes that control multivesicular body formation, endosomal sorting , and transport ubiquitinated membrane proteins (including cell-surface receptors) to the endosomes for degradation. There is accumulating evidence that endosomal dysfunction is linked to neural cell degeneration in vitro, but little is known about the relationship between neural disorders and ESCRT proteins in vivo. Here we specifically deleted the hrs gene, ESCRT-0, in the neurons of mice by crossing loxP-flanked hrs mice with transgenic mice expressing the synapsin-I Cre protein (SynI-cre). Histological analyses revealed that both apoptosis and a loss of hippocampal CA3 pyramidal neurons occurred in the hrs flox/flox ;SynI-cre mice. Notably , the hrs flox/flox ;SynI-cre mice accumulated ubiquitinated proteins , such as glutamate receptors and an autophagy-regulating protein , p62. These molecules are particularly prominent in the hippocampal CA3 neurons and cerebral cortex with advancing age. Accordingly , we found that both locomotor activity and learning ability were severely reduced in the hrs flox/flox ;SynI-cre mice. These data suggest that Hrs plays an important role in neural cell survival in vivo and provide an animal model for neurodegenerative diseases that are known to be commonly affected by the generation of proteinaceous aggregates.

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Mice lacking both subunits of lysosomal β–hexosaminidase display gangliosidosis and mucopolysaccharidosis

Cited by 191 publications

References 8 publications

Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle

Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle

Congenic Analysis of the NKT Cell Control Gene Nkt2 Implicates the Peroxisomal Protein Pxmp4

Loss of Hrs in the Central Nervous System Causes Accumulation of Ubiquitinated Proteins and Neurodegeneration

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