Loss of the cellular prion protein affects the Ca<sup>2+</sup> homeostasis in hippocampal CA1 neurons

Fuhrmann, Martin; Bittner, Tobias; Mitteregger, Gerda; Haider, Nicole; Moosmang, Sven; Kretzschmar, Hans A.; Herms, Jochen

doi:10.1111/j.1471-4159.2006.04011.x

Cited by 69 publications

(58 citation statements)

References 57 publications

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“…In addition to the arrival of new immature granule cells, other PrP-dependent mechanisms may be altered in granule cells once migration is concluded. A reduced L-type Ca 2ϩ -channel expression, which was observed in PrP 0/0 granule cells in culture (Herms et al, 2000;Fuhrmann et al, 2006) (see also Korte et al, 2003), could reduce spike afterhyperpolarization by weakening activation of calcium-dependent K-channels (Colling et al, 1996;Herms et al, 2001) and contribute to alter repetitive spike discharge.…”

Section: Discussionmentioning

confidence: 99%

Altered Neuron Excitability and Synaptic Plasticity in the Cerebellar Granular Layer of Juvenile Prion Protein Knock-Out Mice with Impaired Motor Control

et al. 2008

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Section: Discussionmentioning

confidence: 99%

Altered Neuron Excitability and Synaptic Plasticity in the Cerebellar Granular Layer of Juvenile Prion Protein Knock-Out Mice with Impaired Motor Control

et al. 2008

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“…Toxic peptides of PrP have also been implicated in the alteration of Ca 2+ homeostasis thereby contributing to further ER stress (34). Loss of PrP may also contribute to the disruption of Ca 2+ homeostasis within neurons (35). Furthermore, overexpression of STCH in HEK293 cells sensitized them to tumor necrosis factor-related apoptosis-related ligand (TRAIL)-induced apoptosis, which was abolished by the stomach cancer-derived del223V-226L STCH mutation, which occurs within the ATPbinding domain (36).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the Hspa13 ( Stch ) gene reduces prion disease incubation time in mice

Grizenkova

Akhtar

Hummerich

et al. 2012

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

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Prion diseases are fatal neurodegenerative disorders that include bovine spongiform encephalopathy (BSE) and scrapie in animals and Creutzfeldt-Jakob disease (CJD) in humans. They are characterized by long incubation periods, variation in which is determined by many factors including genetic background. In some cases it is possible that incubation time may be directly correlated to the level of gene expression. To test this hypothesis, we combined incubation time data from five different inbred lines of mice with quantitative gene expression profiling in normal brains and identified five genes with expression levels that correlate with incubation time. One of these genes, Hspa13 (Stch), is a member of the Hsp70 family of ATPase heat shock proteins, which have been previously implicated in prion propagation. To test whether Hspa13 plays a causal role in determining the incubation period, we tested two overexpressing mouse models. The Tc1 human chromosome 21 (Hsa21) transchromosomic mouse model of Down syndrome is trisomic for many Hsa21 genes including Hspa13 and following Chandler/Rocky Mountain Laboratory (RML) prion inoculation, shows a 4% reduction in incubation time. Furthermore, a transgenic model with eightfold overexpression of mouse Hspa13 exhibited highly significant reductions in incubation time of 16, 15, and 7% following infection with Chandler/RML, ME7, and MRC2 prion strains, respectively. These data further implicate Hsp70-like molecular chaperones in protein misfolding disorders such as prion disease.

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“…For example, neurons from PrP-null mice have been reported to display various kinds of electrophysiological abnormalities (52)(53)(54)(55). It has been suggested that PrP C specifically suppresses the activity of a subclass of NMDA-type glutamate receptors based on the demonstration that PrP C physically interacts with the NR2D subunit of these receptors and the fact that neurons from Prn-p Ϫ/Ϫ mice showed enhanced NMDA-evoked currents and were more susceptible to glutamate-induced excitotoxic death (56).…”

Section: Biophysical Characteristics and Molecular Basis Of ⌬Cr Prp-imentioning

confidence: 99%

Neurotoxic Mutants of the Prion Protein Induce Spontaneous Ionic Currents in Cultured Cells

Solomon

Huettner

Harris

2010

Journal of Biological Chemistry

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The mechanisms by which prions kill neurons and the role of the cellular prion protein in this process are enigmatic. Insight into these questions is provided by the neurodegenerative phenotypes of transgenic mice expressing prion protein (PrP) molecules with deletions of conserved amino acids in the central region. We report here that expression in transfected cells of the most toxic of these PrP deletion mutants (⌬105-125) induces large, spontaneous ionic currents that can be detected by patchclamping techniques. These currents are produced by relatively non-selective, cation-permeable channels or pores in the cell membrane and can be silenced by overexpression of wild-type PrP, as well as by treatment with a sulfated glycosaminoglycan. Similar currents are induced by PrP molecules carrying several different point mutations in the central region that cause familial prion diseases in humans. The ionic currents described here are distinct from those produced in artificial lipid membranes by synthetic peptides derived from the PrP sequence because they are induced by membrane-anchored forms of PrP that are synthesized by cells and that are found in vivo. Our results indicate that the neurotoxicity of some mutant forms of PrP is attributable to enhanced ion channel activity and that wild-type PrP possesses a channel-silencing activity. Drugs that block PrP-associated channels or pores may therefore represent novel therapeutic agents for treatment of patients with prion diseases.

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Loss of the cellular prion protein affects the Ca²⁺ homeostasis in hippocampal CA1 neurons

Cited by 69 publications

References 57 publications

Altered Neuron Excitability and Synaptic Plasticity in the Cerebellar Granular Layer of Juvenile Prion Protein Knock-Out Mice with Impaired Motor Control

Altered Neuron Excitability and Synaptic Plasticity in the Cerebellar Granular Layer of Juvenile Prion Protein Knock-Out Mice with Impaired Motor Control

Overexpression of the Hspa13 ( Stch ) gene reduces prion disease incubation time in mice

Neurotoxic Mutants of the Prion Protein Induce Spontaneous Ionic Currents in Cultured Cells

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Loss of the cellular prion protein affects the Ca2+ homeostasis in hippocampal CA1 neurons

Cited by 69 publications

References 57 publications

Altered Neuron Excitability and Synaptic Plasticity in the Cerebellar Granular Layer of Juvenile Prion Protein Knock-Out Mice with Impaired Motor Control

Altered Neuron Excitability and Synaptic Plasticity in the Cerebellar Granular Layer of Juvenile Prion Protein Knock-Out Mice with Impaired Motor Control

Overexpression of the Hspa13 ( Stch ) gene reduces prion disease incubation time in mice

Neurotoxic Mutants of the Prion Protein Induce Spontaneous Ionic Currents in Cultured Cells

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Loss of the cellular prion protein affects the Ca²⁺ homeostasis in hippocampal CA1 neurons