Doxycycline control of prion protein transgene expression modulates prion disease in mice

Tremblay, Patrick; Meiner, Zeev; Galou, Marià; Heinrich, Cornelia; Petromilli, Chris; Lisse, Thomas S.; Cayetano, Juliana; Torchia, Marilyn; Mobley, William C.; Bujard, Hermann; DeArmond, Stephen J.; Prusiner, Stanley B.

doi:10.1073/pnas.95.21.12580

Cited by 167 publications

(97 citation statements)

References 33 publications

(30 reference statements)

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“…inoculation with 2 mg brain tissues from BSE-C-infected cattle (2). It is noteworthy that the Tg650 mice express human PrP-129M at five to eight times the normal level, and high PrP levels are known to increase prion transmissibility (9,17,22). Inefficient BSE-C transmissions (0 to 30%) in Tg mouse lines of other genetic backgrounds expressing human PrP-129M at one or two times the normal level have also been reported by different groups (1,4).…”

Section: Discussionmentioning

confidence: 79%

Evaluation of the Human Transmission Risk of an Atypical Bovine Spongiform Encephalopathy Prion Strain

Kong

Zheng

Casalone³

et al. 2008

J Virol

145

111

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Bovine spongiform encephalopathy (BSE), the prion disease in cattle, was widely believed to be caused by only one strain, BSE-C. BSE-C causes the fatal prion disease named new variant Creutzfeldt-Jacob disease in humans. Two atypical BSE strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L) and BSE-H, have been discovered in several countries since 2004; their transmissibility and phenotypes in humans are unknown. We investigated the infectivity and human phenotype of BASE strains by inoculating transgenic (Tg) mice expressing the human prion protein with brain homogenates from two BASE straininfected cattle. Sixty percent of the inoculated Tg mice became infected after 20 to 22 months of incubation, a transmission rate higher than those reported for BSE-C. A quarter of BASE strain-infected Tg mice, but none of the Tg mice infected with prions causing a sporadic human prion disease, showed the presence of pathogenic prion protein isoforms in the spleen, indicating that the BASE prion is intrinsically lymphotropic. The pathological prion protein isoforms in BASE strain-infected humanized Tg mouse brains are different from those from the original cattle BASE or sporadic human prion disease. Minimal brain spongiosis and long incubation times are observed for the BASE strain-infected Tg mice. These results suggest that in humans, the BASE strain is a more virulent BSE strain and likely lymphotropic.

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Section: Discussionmentioning

confidence: 79%

Evaluation of the Human Transmission Risk of an Atypical Bovine Spongiform Encephalopathy Prion Strain

Kong

Zheng

Casalone³

et al. 2008

J Virol

145

111

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“…A few transgenic strains were then transferred to a FVB/N inbred genetic background. To induce expression of human ATAXIN1 in the brains of transgenic mice, the PrP-tTA (F959 line) (Tremblay et al, 1998) transgenic line was used, which expresses tTA at high levels in all brain regions (Boy et al, 2006).…”

Section: Production and Maintenance Of Tet Transgenic Micementioning

confidence: 99%

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

Giovannoni

Maggio²,

Bianco³

et al. 2007

Neuron Glia Biol.

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Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeats within the coding sequence of the ataxin-1 protein. In the present study, we used a conditional transgenic mouse model of SCA1 to investigate very early molecular and morphological changes related to the behavioral phenotype. In mice with neural deficits detected by rotarod performance, and simultaneous spatial impairments in exploratory activity and uncoordinated gait, we observed both significant altered expression and patchy distribution of excitatory amino acids transporter 1. The molecular changes observed in astroglial compartments correlate with changes in synapse morphology; synapses have a dramatic reduction of the synaptic area external to the postsynaptic density. By contrast, Purkinje cells demonstrate preserved structure. In addition, severe reactive astrocytosis matches changes in the glial glutamate transporter and synapse morphology. We propose these morpho-molecular changes are the cause of altered synaptic transmission, which, in turn, determines the onset of the neurological symptoms by altering the synaptic transmission in the cerebellar cortex of transgenic animals. This model might be suitable for testing drugs that target activated glial cells in order to reduce CNS inflammation.Keywords: EAAT1, synaptic plasticity, SCA1, neurodegeneration INTRODUCTIONThe contribution of non-neuronal cells to the pathogenesis of neurodegenerative diseases has been described although the mechanism remains poorly understood. The role of neuron-glia interactions is also being investigated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (Sheldon and Robinson, 2007). Moreover, glial dysfunction is likely to contribute to the pathogenesis of cerebellar ataxia in a mouse model of spinocerebellar ataxia type 7 (SCA7) (Custer et al., 2006).Excitatory amino acids transporter 1 (EAAT1, also known as GLAST) is the major glutamate transporter in the cerebellum (Lehre and Danbolt, 1998). It is expressed strongly by astrocytes in the molecular layer of the cerebellum and is at highest density on Bergmann glia. EAAT1 is not detected in neurons (Ginsberg et al., 1995). EAAT1 present on the plasma membrane of the astrocytic processes and cell bodies (Chaudhry et al., 1995). Targeting of EAAT1 is regulated carefully on astroglial membranes facing the neuropil, large dendrites, cell bodies and capillary endothelium (Danbolt, 2001). Therefore, its distribution follows the morphological changes of astrocytes during inflammatory processes. Recently, in a mouse model of reactive astrocytosis in the spinal cord, it has been reported that this glial process includes a marked proteolytic cascade having as substrates glial transporters. Subsequent changes in neurotransmitter uptake represent the basis of morphological and functional changes that sustain central plasticity . Moreover, glial activation involves changes in cell phenotype and gene expression that might trig...

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“…Interestingly, the development of spongiform pathologies requires the presence of both isoforms PrP-res and PrP-sen (9), the level of PrP-sen expression being an essential factor in the pathology (10). In experimental transmissions with transgenic mice, it was found that increasing the number of PrP gene copies led to a decreased incubation time of the disease (11,12).…”

Section: Transmissible Spongiform Encephalopathies (Tse)mentioning

confidence: 99%

In Vivo Cytotoxicity of the Prion Protein Fragment 106–126

Ettaiche

Pichot

Vincent

et al. 2000

Journal of Biological Chemistry

123

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Transmissible spongiform encephalopathies are fatal neurological diseases characterized by astroglyosis, neuronal loss, and by the accumulation of the abnormal isoform of the prion protein. The amyloid prion protein fragment 106 -126 (P106 -126) has been shown to be toxic in cultured hippocampal neurons (1). Here, we show that P106 -126 is also cytotoxic in vivo. Taking advantage of the fact that retina is an integral part of the central nervous system, the toxic effect of the peptide was investigated by direct intravitreous injection. Aged solutions of P106 -126 induced apoptotic-mediated retinal cell death and irreversibly altered the electrical activity of the retina. Neither apoptosis nor electroretinogram damages were observed with freshly diluted P106 -126, suggesting that the toxicity is linked to the aggregation state of the peptide. The retina provides a convenient in vivo system to look for potential inhibitors of cytotoxicity associated with spongiform encephalopathies. Transmissible spongiform encephalopathies (TSE)1 are neurological disorders having common pathological signs like vacuolization of the neurophils, astrocytosis, and loss of neurons (2). TSE are characterized by the accumulation of large aggregates of the prion protein, PrP-res, in both human and animal brains. The abnormal PrP-res isoform has a high content of ␤-sheet secondary structure, forms amyloid fibrils, and is partially resistant to proteolysis (3-5). The precursor of the pathological isoform PrP-res is a normal host glycoprotein (termed PrP-sen) widely expressed in the central nervous system and in peripheral tissues. Unlike PrP-res, PrP-sen is a protease-sensitive protein, soluble in mild detergents, and has mainly ␣-helix structures (6 -8). Interestingly, the development of spongiform pathologies requires the presence of both isoforms PrP-res and PrP-sen (9), the level of PrP-sen expression being an essential factor in the pathology (10). In experimental transmissions with transgenic mice, it was found that increasing the number of PrP gene copies led to a decreased incubation time of the disease (11, 12).The in vivo mechanisms leading to the synaptic loss and neuronal death are not elucidated, but the possible involvement of apoptotic processes has been postulated and is consistent with the lack of inflammation stigmata in TSE-affected brains. The neural tissue damages could be due exclusively to PrP-res deposits, and/or to disruption of PrP-sen physiological functions, and/or to cytotoxic effects induced by PrP fragments or PrP-res aggregates. PrP-res and a synthetic peptide fragment (P106 -126) have been shown to be cytotoxic in vitro likely via the programmed cell death pathway (1, 13). Like PrP-res, the P106 -126 peptide is partially resistant to proteinase K, presents a high ␤-sheet enriched structure, and forms amyloid fibrils in vitro (14). Hope et al. (15) have shown that the expression of PrP-sen is necessary for P106 -126 to exert its cytotoxic effects.Whether the apoptotic process could account for in vivo neuro...

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Doxycycline control of prion protein transgene expression modulates prion disease in mice

Abstract: ABSTRACT

Cited by 167 publications

References 33 publications

Evaluation of the Human Transmission Risk of an Atypical Bovine Spongiform Encephalopathy Prion Strain

Evaluation of the Human Transmission Risk of an Atypical Bovine Spongiform Encephalopathy Prion Strain

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

In Vivo Cytotoxicity of the Prion Protein Fragment 106–126

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