Neurotoxicity and Neurodegeneration When PrP Accumulates in the Cytosol

Ma, Jiyan; Wollmann, Robert; Lindquist, Susan

doi:10.1126/science.1073725

Cited by 451 publications

(416 citation statements)

References 39 publications

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“…It has been shown that accumulation of unglycosylated PrP can be neurotoxic for transgenic mice that develop a severe ataxia, with cerebellar degeneration and gliosis (58). This is not the case in our transgenics, since the mice with accumulation of intracellular PrP did not develop any type of neurodegeneration even after a prolonged period.…”

Section: Discussioncontrasting

confidence: 53%

Altered Glycosylated PrP Proteins Can Have Different Neuronal Trafficking in Brain but Do Not Acquire Scrapie-like Properties

Cancellotti

Wiseman

Tuzi

et al. 2005

Journal of Biological Chemistry

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N-Linked glycans have been shown to have an important role in the cell biology of a variety of cell surface glycoproteins, including PrP protein. It has been suggested that glycosylation of PrP can influence the susceptibility to transmissible spongiform encephalopathy and determine the characteristics of the many different strains observed in this particular type of disease. To understand the role of carbohydrates in influencing the PrP maturation, stability, and cell biology, we have produced and analyzed gene-targeted murine models expressing differentially glycosylated PrP. Transgenic mice carrying the PrP substitution threonine for asparagine 180 (G1) or threonine for asparagine 196 (G2) or both mutations combined (G3), which eliminate the first, second, and both glycosylation sites, respectively, have been generated by double replacement gene targeting. An in vivo analysis of altered PrP has been carried out in transgenic mouse brains, and our data show that the lack of glycans does not influence PrP maturation and stability. The presence of one chain of sugar is sufficient for the trafficking to the cell membrane, whereas the unglycosylated PrP localization is mainly intracellular. However, this altered cellular localization of PrP does not lead to any overt phenotype in the G3 transgenic mice. Most importantly, we found that, in vivo, unglycosylated PrP does not acquire the characteristics of the aberrant pathogenic form (PrP Sc ), as was previously reported using in vitro models.

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Section: Discussioncontrasting

confidence: 53%

Altered Glycosylated PrP Proteins Can Have Different Neuronal Trafficking in Brain but Do Not Acquire Scrapie-like Properties

Cancellotti

Wiseman

Tuzi

et al. 2005

Journal of Biological Chemistry

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“…It has been proposed that the accumulation of PrP sc within the cytosol of the neuron results in the death of nerve cells. 9 The 90-120 amino acid region of the PrP is regarded to be functionally important for the conversion of PrP c into PrP sc , and this region is highly homologous in various species, including mouse, hamster and human. 10,11 Antibodies to this domain of the PrP have been generated by several groups of researchers for studying PrP sc and its propagation, as all of these antibodies can recognize both PrP c and PrP sc .…”

Section: Introductionmentioning

confidence: 99%

Detection of prion epitopes on PrP^c and PrP^sc of transmissible spongiform encephalopathies using specific monoclonal antibodies to PrP

et al. 2005

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Summary Amino acid residues 90-120 of the prion protein (PrP) are likely to be critical for the conversion of PrP c to PrP sc in the transmissible spongiform encephalopathies. We raised 10 monoclonal antibodies against the 90-120 amino acid region, mapped the epitope specificity of these anti-PrP antibodies, and investigated the expression of epitopes recognized by the antibodies in both PrP c and PrP sc . Four out of five of the anti-PrP antibodies raised in a prion knockout mouse immunized with the linear peptide of PrP90-120 could detect PrP sc in 'native' and denatured forms and PrP c in normal cells, as well as recognize epitopes within PrP93-112 residues. In contrast, the other six anti-PrP reagents, including five raised from the two knockout mice immunized with conformationally modified PrP90-120 peptide, could detect PrP c and recognize epitopes within PrP93-107 residues. Four of these reagents could also detect denatured PrP sc on western blots but not PrP sc plaques in brain tissue. The results indicate that residues PrP93-102 are exposed in PrP c but are buried upon conversion to the PrP sc isoform. Furthermore, PrP103-107 residues are partially buried in PrP sc while only the PrP107-112 epitope remains exposed, suggesting that the region PrP93-112 undergoes conformational changes during its conversion to PrP sc .

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“…We therefore examined various combinations of cell death stimuli and cell lines and found that the proteasome inhibitor MG132 induced a slow apoptosis process in Neuro 2a cells, a mouse neuroblastoma cell line. Neuro 2a cells were exposed to MG132 18 and then stained with the AE-4 anti-H1 antibody, the anti-active caspase-3 antibody, and Hoechst dye, at different time points.…”

Section: Resultsmentioning

confidence: 99%

Caspase-mediated changes in histone H1 in early apoptosis: prolonged caspase activation in developing olfactory sensory neurons

et al. 2008

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Programmed cell death or apoptosis is required for the patterning and development of multicellular organisms. However, apoptosis is a difficult process to measure because the dead cells are rapidly degraded by their neighbors within a few hours. The post-caspase activation events that determine whether a cell will undergo apoptosis remain elusive. Here we report that apoptosis-specific nuclear events that occur before DNA fragmentation can be distinguished by monitoring the histone H1 status. In both mammals and Drosophila, dying cells failed to be immunolabeled with an anti-H1 monoclonal antibody, AE-4. Real-time imaging of caspase activation and H1 dynamics in mammalian neural cells revealed that H1 changed its location in the nucleus after caspase activation. In addition, the timing of this re-localization was largely dependent on the apoptotic stimulus used. From the staining patterns of AE-4 and anti-active caspase-3 antibodies, cells undergoing the transition from caspase activation to the apoptotic H1 change could be identified as H1-positive caspase-activated cells, providing a novel criterion for early apoptosis and making it possible to characterize caspase-activated cells in tissues. On the basis of these staining patterns, we found that many olfactory sensory neurons in the developing mouse olfactory epithelium showed sustained caspase activity without the H1 change, suggesting a unique caspase function in these neurons.

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Neurotoxicity and Neurodegeneration When PrP Accumulates in the Cytosol

Cited by 451 publications

References 39 publications

Altered Glycosylated PrP Proteins Can Have Different Neuronal Trafficking in Brain but Do Not Acquire Scrapie-like Properties

Altered Glycosylated PrP Proteins Can Have Different Neuronal Trafficking in Brain but Do Not Acquire Scrapie-like Properties

Detection of prion epitopes on PrP^c and PrP^sc of transmissible spongiform encephalopathies using specific monoclonal antibodies to PrP

Caspase-mediated changes in histone H1 in early apoptosis: prolonged caspase activation in developing olfactory sensory neurons

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Neurotoxicity and Neurodegeneration When PrP Accumulates in the Cytosol

Cited by 451 publications

References 39 publications

Altered Glycosylated PrP Proteins Can Have Different Neuronal Trafficking in Brain but Do Not Acquire Scrapie-like Properties

Altered Glycosylated PrP Proteins Can Have Different Neuronal Trafficking in Brain but Do Not Acquire Scrapie-like Properties

Detection of prion epitopes on PrPc and PrPsc of transmissible spongiform encephalopathies using specific monoclonal antibodies to PrP

Caspase-mediated changes in histone H1 in early apoptosis: prolonged caspase activation in developing olfactory sensory neurons

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Detection of prion epitopes on PrP^c and PrP^sc of transmissible spongiform encephalopathies using specific monoclonal antibodies to PrP