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PubMed2006

Monitoring the growth effect of xenotransplanted human medulloblastoma in an immunocompromised mouse model using in vitro and ex vivo green fluorescent protein imaging.

INTRODUCTION: Medulloblastoma (MB) is one of the most common malignant brain tumors in children. It is a radiosensitive tumor. At 5 years after radical surgical excision and craniospinal axis irradiation, the tumor-free survival rate is from 50 to 70% [Halperin EC, Constine LS, Tarbell NJ, Kun LE. Pediatric radiation oncology (2005)]. CASE REPORT: In this study, we established xenotransplanted human MB (hMB) cells - isochromosome 17q - in a severe combined immunodeficiency (SCID) mouse model. We further transduced green fluorescent protein (GFP) into hMB cells to evaluate these hMB cells grafted in SCID mice. RESULTS: The result of an ex vivo GFP imaging system showed that a small lesion of the third-week-hMB-transplanted graft presented "green" signals with a clear tumor margin before any tumor-related symptoms were noted. We also demonstrated that the tumor progression could be monitored by GFP imaging for up to 12 weeks post-transplantation. CONCLUSIONS: This novel approach of GFP imaging assessment provides more accurate information of tumor status for experimental brain tumor studies. Because MB is sensitive to radiation and also response to chemotherapy, this SCID mouse model will be helpful for preclinical studies in the future.

Animals↗
PubMed2003

Toxicological aspects of treatment to remove cyanobacterial toxins from drinking water determined using the heterozygous P53 transgenic mouse model.

The presence of toxic cyanobacteria in drinking water reservoirs renders the need to develop treatment methods for the 'safe' removal of their associated toxins. Chlorine has been shown to successfully remove a range of cyanotoxins including microcystins, cylindrospermopsin and saxitoxins. Each cyanotoxin requires specific treatment parameters, particularly solution pH and free chlorine residual. However, currently there has not been any investigation into the toxicological effect of solutions treated for the removal of these cyanotoxins by chlorine. Using the P53(def) transgenic mouse model male and female C57BL/6J hybrid mice were used to investigate potential cancer inducing effects from such oral dosing solutions. Both purified cyanotoxins and toxic cell-free extract cyanobacterial solutions were chlorinated and administered over 90 and 170 days (respectively) in drinking water. No increase in cancer was found in any treatment. The parent cyanotoxins, microcystins, cylindrospermopsin and saxitoxins were readily removed by chlorine. There was no significant increase in the disinfection by-products trihalomethanes or haloacetic acids, levels found were well below guideline values. Histological examination identified no effect of treatment solutions except male mice treated with chlorinated cylindrospermopsin (as a cell free extract). In this instance 40% of males were found to have fatty vacuolation in their livers, cause unknown. It is recommended that further toxicology be undertaken on chlorinated cyanobacterial solutions, particularly for non-genotoxic carcinogenic compounds, for example the Tg. AC transgenic mouse model.

Acetates↗
PubMed2005

Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy.

OBJECTIVE: We studied a transgenic mouse model of human desmin-related cardiomyopathy with cardiac-specific expression of a 7-amino acid deletion mutation in desmin (D7-des) to test the hypothesis that impaired linkage between desmin and desmosomes alters expression and function of the electrical coupling protein, connexin43 (Cx43). METHODS: Expression of Cx43 and selected mechanical junctions proteins was characterized in left ventrices of D7-des and control mice by quantitative confocal microscopy and immunoblotting. Remodeling of gap junctions was also analyzed by electron microscopic morphometry. The electrophysiological phentoype of D7-des mice was characterized by electrocardiography and optical mapping of transmembrane voltage. RESULTS: Cx43 signal at intercalated disks was decreased by approximately 3-fold in D7-des ventricular tissue due to reductions in both gap junction number and size. Immunoreactive signal at cell-cell junctions was also reduced significantly for adhesion molecules and linker proteins of desmosomes and fascia adherens junctions. Electron microscopy showed decreased gap junction remodeling. However, immunoblotting showed that the total tissue content of Cx43 and mechanical junction proteins was not reduced, suggesting that diminished signal at cell-cell junctions was not due to insufficient protein expression, but to failure of these proteins to assemble properly within electrical and mechanical junctions. Remodeling of gap junctions in D7-des mice led to slowing of ventricular conduction as demonstrated by optical electrophysiological mapping. CONCLUSIONS: These results illustrate how a defect in a protein conventionally thought to fulfill a mechanical function in the heart can also lead to electrophysiological alterations that may contribute to arrhythmogenesis.

Animals↗
PubMed2003

A genetic mouse model carrying the nonfunctional xeroderma pigmentosum group G gene.

A genetic mouse model with a disrupted XPG allele was generated by insertion of neo cassette sequences into exon 3 of the XPG gene by using embryonic stem (ES) cell techniques. The xpg-deficient mice showed distinct developmental characteristics. Their body was marked smaller than that in wild-type littermates since the postnatal day 6, and this postnatal growth failure became more severe with developmental proceeding. Their life span was very short, all of the mutants died by postnatal day 23 after showing great weakness and emaciation. In addition, the mutant homozygous mice also showed some progressive neurological signs, like the lower level of activity and a progressive ataxia. Further examination indicated there was developmental retardation of the brain in the mutant mice. Their brain weight, and thickness of cerebral cortex and cerebellar cortex were significant different from the controls. These characteristics, like small size brain, brain developmental retardation and progressive neurological dysfunctions in the homozygotes were similar to the typical clinical phenotype of the XPG patients and Cockayne syndrome, we believe that the xpgdeficient mice will be an animal model for studying the function of the XP-G protein in nucleotide-excision repair and mechanisms related to the clinic symptoms of XP-G and Cockayne syndrome in humans.

Animals↗
PubMed2000

The topoisomerase I inhibitor DX-8951f is active in a severe combined immunodeficient mouse model of human acute myelogenous leukemia.

The severe combined immunodeficient (SCID) mouse model of human acute myelogenous leukemia (AML) is a unique system for preclinical in vivo evaluation of the activity and toxicity of new agents. The topoisomerase I (topo I) inhibitor topotecan is active in patients with AML and myelodysplastic syndromes. DX-8951f is a novel topo I inhibitor with more potent antitumor effects than topotecan or CPT-11 in vitro. To study the in vivo activity of DX-8951f, 6-week-old female SCID mice received injections into the tail vein with 2 x 10(7) exponentially growing KBM-3 cells. In each experiment, three to five sets of five mice were treated with DX-8951f doses ranging from 7.5 to 80 mg/kg and at schedules of 1, 3, and 5 days; a control set of five mice was treated with the drug vehicle alone. One group received DX-8951f on day 7 of the inoculation with KBM-3 (early-treatment group). To study the activity of DX-8951f in advanced disease, a second group was treated 1 month after the inoculation, when the animals were developing symptoms (late-treatment group). The study end point was the duration of survival until death from leukemia, which was assessed clinically and by the presence of the human DQ alpha gene in tissue samples by PCR. Six experiments were conducted with 170 animals. Survival was higher in both the early- and late-treatment groups than in untreated controls, and the treated groups had significantly less central nervous system disease. Significantly improved survival was observed in animals treated early with 60 and 80 mg/kg as a single injection, with 15 and 20 mg/kg over 3 days, and with 7.5 and 10 mg/kg over 5 days. In the late-disease model (treatment starting on days 28-35), improved survival was observed with a single dose of 80 or 20 mg/kg over 5 days. Dose escalation was limited by dilution problems at the 1-day schedule and by toxicity (mainly gastrointestinal) of the prolonged schedules. Both efficacy and toxicity were dose schedule dependent, increasing with higher doses and prolonged exposure. By establishing the antileukemic activity of DX-8951f against human AML transplanted into SCID mice at doses below the LD10, our data provide a rationale for clinical evaluation of the drug in patients with AML and favor the use of prolonged administration.

Animals↗
PubMed1995

Loss of myelinated axons is specific to the central nervous system in a mouse model of the fetal alcohol syndrome.

We have previously developed a mouse model of the fetal alcohol syndrome, the outcome of which is a late loss of myelinated axons in the optic nerve of offspring of alcohol-treated mice between 9 and 15 wk of age. We have extended this study to investigate whether this axon loss is stable and specific to the central nervous system. Pregnant female (C57BL/6/Wlds x CBA) F1 mice were injected intraperitoneally with a single dose of a 25% solution of ethanol (v:w), on d 12 of gestation. Control animals were given a similar volume of saline at the same time. Litters were taken at 12 (n = 18) and 23 (n = 26) wk of age. Optic nerves only from 12-wk-old, and optic, tibial and saphenous nerves from 23-wk-old mice were removed. A systematic, random sampling method was used to estimate the cross-sectional area of whole nerves from semi thin sections, and the numbers and diameters of myelinated axons from ultrathin sections. There were no differences for the optic nerves of 12-wk-old alcohol-treated and control animals. Optic nerves from the alcohol-treated group at 23 wk had smaller cross-sectional areas and approximately 17% fewer myelinated axons than control nerves. These results confirm that axon loss occurs between 12 and 15 wk, and demonstrate that there is no additional loss of myelinated axons between 15 and 23 wk. In contrast, there were no significant differences in cross-sectional area, number of myelinated axons or axon calibre spectra for the tibial and saphenous nerves between the alcohol-treated and control groups. There was thus no evidence of a peripheral neuropathy as has been observed in chronic alcoholic subjects. In this 'binge' model of the fetal alcohol syndrome, a carefully timed dose of alcohol is administered during pregnancy to coincide with a critical period of development of the visual system. The result is a teratogenic effect which is specific to the central nervous system, stable and reproducible, with no obvious effect on the peripheral nervous system.

Animals↗
PubMed2003

Spatial and temporal distribution of intracellular free cholesterol in brains of a Niemann-Pick type C mouse model showing hyperphosphorylated tau protein. Implications for Alzheimer's disease.

Niemann-Pick type C (NPC) disease is a fatal hereditary neurovisceral disorder with diagnostically relevant intracellular accumulation of cholesterol in non-brain tissue, for example the spleen and fibroblasts. In the brain, many ballooned neurons are seen. Using filipin microfluorodensitometry, significant accumulations of free cholesterol in specified neurons have been described in NPC patients. The present study demonstrates spatial and temporal accumulation of free cholesterol in the brains of homozygous NPC (-(npc)/-(npc)) mice, a widely acknowledged mouse model, and in primarily cultured neurons therefrom. Intraneuronal storage of free cholesterol was already prominent at a pre-clinical stage in various grey matter areas of the murine cerebral cortex. Hippocampal areas showed differential development of the pathological distribution of free cholesterol. The pyramidal cells in the CA3 sector of Ammon's horn were affected much earlier than in CA1. Some of the deeper cerebral nuclei were affected only slightly, even at the final stage. Neurons (E15-E17) cultured in a cholesterol-free medium also showed massive accumulation of intracellular free cholesterol. In addition, brains from the murine NPC model for Alzheimer's disease (AD)-like changes in the microtubule-associated protein tau were tested using the Gallyas silver technique and AT8-immunolabelling, since both human diseases are accompanied by intraneuronal tangles made up of tau protein aggregations. Although the analysis failed to show classical silver-stainable tangles of the AD type in the NPC mice, tau protein phosphorylated at epitopes considered to represent early stages of AD was found. This further strengthens the concept that an alteration in cholesterol metabolism may play an important role in AD. The NPC mouse model may thus serve as a tool to analyse the role of cholesterol in initial changes of tau that eventually lead to the formation of tangles in both NPC and AD.

Alzheimer Disease↗
PubMed2004

Allergen-loaded biodegradable poly(D,L-lactic-co-glycolic) acid nanoparticles down-regulate an ongoing Th2 response in the BALB/c mouse model.

BACKGROUND AND OBJECTIVE: Biocompatible and biodegradable microparticles have gained interest as antigen delivery systems during the recent years. We investigated whether biodegradable poly(d,l-lactic-co-glycolic) acid (PLGA) nanospheres could be used as allergen vehicles for few-shot therapy of type I allergy. METHODS: The major birch pollen allergen Bet v 1 was encapsulated in PLGA nanospheres (PLGA-Bet v 1). We examined the antigenicity and the immune response to PLGA-Bet v 1 in a BALB/c mouse model. RESULTS: The antigenicity of Bet v 1 was largely unaffected by PLGA entrapment. When BALB/c mice were immunized subcutaneously with PLGA-Bet v 1, they formed allergen-specific IgG antibodies, but did not develop hypersensitivity to Bet v 1, as shown by type I skin tests. To evaluate their therapeutic potential, PLGA-Bet v 1 with or without Al(OH)3 or non-entrapped Bet v 1 with Al(OH)3 were used for single-shot treatment of sensitized mice. Both groups treated with PLGA-Bet v 1 developed high levels of Bet v 1-specific IgG2a antibodies (P<0.01), whereas IgG1 levels decreased significantly (P<0.01). Moreover, T cells from mice treated with PLGA-Bet v 1 showed IFN-gamma and IL-10 production. The synthesis of these cytokines was enhanced in the groups where Al(OH)3 had been added to the vaccine formulation. CONCLUSION: Allergen-loaded PLGA nanoparticles modulate an ongoing Th2 response in the BALB/c mouse model, as demonstrated by down-regulation of IgG1 and production of IFN-gamma and IL-10. Our data strongly suggest that PLGA nanospheres can advantageously be used for formulations of allergen extracts or allergen derivatives for the few-shot treatment of type I allergy.

Allergens↗
PubMed2004

Synaptic structural abnormalities in the Ts65Dn mouse model of Down Syndrome.

The Ts65Dn mouse is a genetic model for Down syndrome. Although this mouse shows abnormalities in cognitive function that implicate hippocampus as well as marked deficits in hippocampal long-term potentiation, the structure of the hippocampus has been little studied. We characterized synaptic structure in Ts65Dn and control (2N) mice, studying the hippocampus (fascia dentata, CA1) as well as the motor and somatosensory cortex, entorhinal cortex, and medial septum. Confocal microscopy was used to examine immunostained presynaptic boutons and to detail the structure of dendrites after Lucifer yellow microinjection. Both presynaptic and postsynaptic elements were significantly enlarged in Ts65Dn in all regions examined. The changes were detected at the youngest age examined (postnatal day 21) and in adults. In studies detailing the changes in fascia dentata and motor cortex, the enlargement of spines affected the entire population, resulting in the presence of spines whose volume was greatly increased. Electron microscopy confirmed that boutons and spines were enlarged and demonstrated abnormalities in the internal membranes of both. In addition, spine density was decreased on the dendrites of dentate granule cells, and there was reorganization of inhibitory inputs, with a relative decrease in inputs to dendrite shafts and an increase in inputs to the necks of spines. Taken together, the findings document widespread abnormalities of synaptic structure that recapitulate important features seen in Down syndrome. They establish the Ts65Dn mouse as a model for abnormal synapse structure and function in Down syndrome and point to the importance of studies to elucidate the mechanisms responsible for synapse enlargement.

Animals↗
PubMed1985

Anticonvulsant action of GABA agonists and prodrugs on minor and major seizures in epileptic gerbils. Comparison with mouse models of seizure states.

The anticonvulsant efficacy of the GABAmimetic drugs cetyl GABA, progabide and THIP (4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol) was studied against minor (myoclonic) and major (generalized tonic-clonic) seizures in gerbils as well as against maximal electroshock and s.c. pentylenetetrazol-induced seizures in mice. Seizures in gerbils were evoked by a blast of compressed air. THIP and progabide were about equally active to protect gerbils against minor and major seizures. ED 50s for THIP were 0.98 and 1.3 mg/kg and for progabide 58 and 50 mg/kg i.p., respectively. Cetyl GABA failed to show a linear dose-response against minor seizures but was quite potent against major ones (ED 50 4.4 mg/kg). All three GABAmimetics were inactive in the mouse models of seizure states except a weak effect of progabide against maximal electroshock seizures. The data show that seizure-prone gerbils with different seizure types differ strikingly in sensitivity to GABAmimetic drugs from traditional mouse models for anticonvulsant drug evaluation.

Animals↗
PubMed2006

Caspase activation and apoptosis induction by adalimumab: demonstration in vitro and in vivo in a chimeric mouse model.

BACKGROUND: Adalimumab is a fully human monoclonal antibody to tumor necrosis factor (TNF), which was recently introduced as a therapy for Crohn's disease and rheumatoid arthritis. Besides neutralization, induction of apoptosis of monocytes/macrophages and T cells is thought to be an important mechanism of action of the anti-tumor necrosis factor monoclonal antibody infliximab, at least in Crohn's disease therapy. AIM: To study caspase activation and the induction of apoptosis by adalimumab and the effect of a caspase inhibitor in vivo. METHODS: For in vitro studies, THP-1 cells (human monocytic cell line) were incubated with adalimumab, infliximab, or human immunoglobulin G, and annexin V + propidium iodide, Apo2.7, and 7-amino actinomycin-D were used to study apoptosis on the cell membrane, mitochodrial, and DNA level, respectively. Active caspase-3 was detected by intracellular staining. For in vivo studies, a chimeric human-mouse model was used, in which THP-1 cells were injected intraperitoneally in SCID-Beige mice followed by treatment with adalimumab, infliximab, or human immunoglobulin G. Effects of a pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyketone on apoptosis induction were evaluated. RESULTS: In vitro analysis revealed that apoptosis could be induced in THP-1 cells by both adalimumab and infliximab. Activation of caspase-3 after incubation with adalimumab was demonstrated by intracellular staining. In addition, in the chimeric mouse model, a higher percentage of residual THP-1 cells were apoptotic, and lower cell numbers were recovered in the adalimumab- or infliximab-treated mouse. Apoptosis induction by adalimumab could be abrogated through in vivo pretreatment of mice with the pan-caspase inhibitor. CONCLUSIONS: Adalimumab, besides neutralizing tumor necrosis factor, also induces apoptosis of transmembrane tumor necrosis factor-positive THP-1 cells by activating intracellular caspases. This activity is likely to be important for the clinical effect of this biodrug.

Adalimumab↗
PubMed2006

Mouse models in non-alcoholic fatty liver disease and steatohepatitis research.

Non-alcoholic fatty liver disease (NAFLD) represents a histological spectrum of liver disease associated with obesity, diabetes and insulin resistance that extends from isolated steatosis to steatohepatitis and cirrhosis. As well as being a potential cause of progressive liver disease in its own right, steatosis has been shown to be an important cofactor in the pathogenesis of many other liver diseases. Animal models of NAFLD may be divided into two broad categories: those caused by genetic mutation and those with an acquired phenotype produced by dietary or pharmacological manipulation. The literature contains numerous different mouse models that exhibit histological evidence of hepatic steatosis or, more variably, steatohepatitis; however, few replicate the entire human phenotype. The genetic leptin-deficient (ob/ob) or leptin-resistant (db/db) mouse and the dietary methionine/choline-deficient model are used in the majority of published research. More recently, targeted gene disruption and the use of supra-nutritional diets to induce NAFLD have gained greater prominence as researchers have attempted to bridge the phenotype gap between the available models and the human disease. Using the physiological processes that underlie the pathogenesis and progression of NAFLD as a framework, we review the literature describing currently available mouse models of NAFLD, highlight the strengths and weaknesses of established models and describe the key findings that have furthered the understanding of disease pathogenesis.

Adipose Tissue↗
PubMed2005

The development of a mouse model of ovarian endosalpingiosis.

Pelvic pain is a common presenting ailment in women often linked to ovulation, endometriosis, early pregnancy, ovarian cancer, and cysts. Clear differential diagnosis for each condition caused by these varied etiologies is difficult and may slow the delivery of therapy that, in the case of ovarian cancer, could be fatal. Ovarian endosalpingiosis, a pelvic condition typified by the presence of cystic glandular structures lined by benign tubal/salpingeal epithelium, is also associated with pelvic pain in women. The exact cellular antecedents of these epithelial lined cystic structures are not known, nor is there a known link to ovarian cancer. A mouse model of ovarian endosalpingiosis has been developed by directing a dominant-negative version of the TGF-beta transcription factor, Smad2, to the ovary using the Müllerian-inhibiting substance promoter (MIS-Smad2-dn). Female mice develop an ovarian endosalpingeal phenotype as early as 3 months of age. Importantly, cysts continuous with the ovarian surface epithelial have been identified, indicating that these cyst cells may be derived from the highly plastic ovarian surface epithelial cell layer. A second transgenic mouse model that causes loss of activin action (inhibin alpha-subunit transgenic mice) develops similar cystic structures, supporting a TGF-beta/activin/Smad2 dependence in the onset of this disease.

Activins↗
PubMed1990

The relationship of excess copper accumulation by fibroblasts from the brindled mouse model of Menkes disease to the primary defect.

Fibroblasts from the brindled mouse model of Menkes disease are known to accumulate excess copper. Most of the copper in the cytosol of these fibroblasts is bound to metallothionein (MT), which is elevated in Menkes or brindled mouse fibroblasts. Copper accumulation by normal fibroblasts containing excess MT was examined to determine if the excess copper accumulation phenotype was secondary to excess MT or associated with the primary defect in fibroblasts from the brindled mice. MT was induced in normal fibroblasts by copper, zinc or dexamethasone to levels comparable with those in brindled mice fibroblasts, as determined by radioimmunoassays. Normal fibroblasts containing excess MT accumulate copper normally, i.e. they do not exhibit the excess copper accumulation phenotype. Consistent with this result, copper efflux from normal fibroblasts containing excess MT was also normal. The data suggest that one function of the protein associated with the primary defect is to help determine how much copper is taken up and retained by fibroblasts and other cell types exhibiting the excess copper phenotype in Menkes disease. The capacity of this protein is apparently exceeded in normal fibroblasts if serum or albumin is not present extracellularly to limit total copper uptake. Consistent with a defect in an intracellular protein, the kinetics of copper transport by brindled mice fibroblasts were found to be normal.

Animals↗
PubMed1999

TGF-beta1 in liver fibrosis: an inducible transgenic mouse model to study liver fibrogenesis.

Transforming growth factor-beta1 (TGF-beta1) is a powerful stimulus for collagen formation in vitro. To determine the in vivo effects of TGF-beta1 on liver fibrogenesis, we generated transgenic mice overexpressing a fusion gene [C-reactive protein (CRP)/TGF-beta1] consisting of the cDNA coding for an activated form of TGF-beta1 under the control of the regulatory elements of the inducible human CRP gene promoter. Two transgenic lines were generated with liver-specific overexpression of mature TGF-beta1. After induction of the acute phase response (15 h) with lipopolysaccharide (100 microgram ip), plasma TGF-beta1 levels reached >600 ng/ml in transgenic animals, which is >100 times above normal plasma levels. Basal plasma levels of uninduced transgenic animals were about two to five times above normal. As a consequence of hepatic TGF-beta1 expression, we could demonstrate marked transient upregulation of procollagen I and procollagen III mRNA in the liver 15 h after the peak of TGF-beta1 expression. Liver histology after repeated induction of transgene expression showed an activation of hepatic stellate cells in both transgenic lines. The fibrotic process was characterized by perisinusoidal deposition of collagen in a linear pattern. This transgenic mouse model gives in vivo evidence for the important role of TGF-beta1 in stellate cell activation and liver fibrogenesis. Due to the ability to control the level of TGF-beta1 expression, this model allows the study of the regulation and kinetics of collagen synthesis and fibrolysis as well as the degree of reversibility of liver fibrosis. The CRP/TGF-beta1 transgenic mouse model may finally serve as a model for the testing of antifibrogenic agents.

Animals↗
PubMed2006

Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy.

X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a polyglutamine (polyQ) disease in which the affected males suffer progressive motor neuron degeneration accompanied by signs of androgen insensitivity, such as gynecomastia and reduced fertility. SBMA is caused by CAG repeat expansions in the androgen receptor (AR) gene resulting in the production of AR protein with an extended glutamine tract. SBMA is one of nine polyQ diseases in which polyQ expansion is believed to impart a toxic gain-of-function effect upon the mutant protein, and initiate a cascade of events that culminate in neurodegeneration. However, whether loss of a disease protein's normal function concomitantly contributes to the neurodegeneration remains unanswered. To address this, we examined the role of normal AR function in SBMA by crossing a highly representative AR YAC transgenic mouse model with 100 glutamines (AR100) and a corresponding control (AR20) onto an AR null (testicular feminization; Tfm) background. Absence of endogenous AR protein in AR100Tfm mice had profound effects upon neuromuscular and endocrine-reproductive features of this SBMA mouse model, as AR100Tfm mice displayed accelerated neurodegeneration and severe androgen insensitivity in comparison to AR100 littermates. Reduction in size and number of androgen-sensitive motor neurons in the spinal cord of AR100Tfm mice underscored the importance of AR action for neuronal health and survival. Promoter-reporter assays confirmed that AR transactivation competence diminishes in a polyQ length-dependent fashion. Our studies indicate that SBMA disease pathogenesis, both in the nervous system and the periphery, involves two simultaneous pathways: gain-of-function misfolded protein toxicity and loss of normal protein function.

Androgen-Insensitivity Syndrome↗
PubMed1999

Misexpression of the opaque-phase-specific gene PEP1 (SAP1) in the white phase of Candida albicans confers increased virulence in a mouse model of cutaneous infection.

Candida albicans WO-1 switches reversibly and at high frequency between a white and an opaque colony-forming phenotype that includes dramatic changes in cell morphology and physiology. A misexpression strategy has been used to investigate the role of the opaque-phase-specific gene PEP1 (SAP1), which encodes a secreted aspartyl proteinase, in the expression of the unique opaque-phase phenotype and phase-specific virulence in two animal models. The PEP1 (SAP1) open reading frame was inserted downstream of the promoter of the white-phase-specific gene WH11 in the transforming vector pCPW7, and the resulting transformants were demonstrated to misexpress PEP1 (SAP1) in the white phase. Misexpression did not confer any of the unique morphological characteristics of the opaque phase to cells in the white phase and had no effect on the switching process. However, misexpression conferred upon white-phase cells the increased capacity of opaque-phase cells to grow in medium in which protein was the sole nitrogen source. Misexpression of PEP1 (SAP1) had no effect on the virulence of white-phase cells in a systemic mouse model, in which white-phase cells were already more virulent than opaque-phase cells. Misexpression did, however, confer upon white-phase cells the dramatic increase in colonization of skin in a cutaneous mouse model that was exhibited by opaque-phase cells. Misexpression of PEP1 (SAP1) conferred upon white-phase cells two dissociable opaque-phase characteristics: increased adhesion and the capacity to cavitate skin. The addition of pepstatin A to the cutaneous model inhibited the latter, but not the former, suggesting that the latter is effected by released enzyme, while the former is effected by cell-associated enzyme.

Animals↗
PubMed1997

Mouse model of GM2 activator deficiency manifests cerebellar pathology and motor impairment.

The GM2 activator deficiency (also known as the AB variant), Tay-Sachs disease, and Sandhoff disease are the major forms of the GM2 gangliosidoses, disorders caused by defective degradation of GM2 ganglioside. Tay-Sachs and Sandhoff diseases are caused by mutations in the genes (HEXA and HEXB) encoding the subunits of beta-hexosaminidase A. The GM2 activator deficiency is caused by mutations in the GM2A gene encoding the GM2 activator protein. For degradation of GM2 ganglioside by beta-hexosamindase A, the GM2 activator protein must participate by forming a soluble complex with the ganglioside. In each of the disorders, GM2 ganglioside and related lipids accumulate to pathologic levels in neuronal lysosomes, resulting in clinically similar disorders with an onset in the first year of life, progressive neurodegeneration, and death by early childhood. We previously have described mouse models of Tay-Sachs (Hexa -/-) and Sandhoff (Hexb -/-) diseases with vastly different clinical phenotypes. The Hexa -/- mice were asymptomatic whereas the Hexb -/- mice were severely affected. Through gene disruption in embryonic stem cells we now have established a mouse model of the GM2 activator deficiency that manifests an intermediate phenotype. The Gm2a -/- mice demonstrated neuronal storage but only in restricted regions of the brain (piriform, entorhinal cortex, amygdala, and hypothalamic nuclei) reminiscent of the asymptomatic Tay-Sachs model mice. However, unlike the Tay-Sachs mice, the Gm2a -/- mice displayed significant storage in the cerebellum and defects in balance and coordination. The abnormal ganglioside storage in the Gm2a -/- mice consisted of GM2 with a low amount of GA2. The results demonstrate that the activator protein is required for GM2 degradation and also may indicate a role for the GM2 activator in GA2 degradation.

Animals↗