Regulation of intracellular free calcium levels by the cellular prion protein

Whatley, Stephen A.; Powell, John; Politopoulou, Galatia; Campbell, Iain C.; Brammer, Michael; Percy, Neville S.

doi:10.1097/00001756-199511270-00015

Cited by 59 publications

(38 citation statements)

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“…However, evidence indicates that PrP may promote sleep continuity (10). PrP is involved in the regulation of presynaptic copper concentration, intracellular calcium concentration, activation of lymphocytes, astrocyte proliferation, and signal transduction and has antioxidant properties (11)(12)(13)(14)(15)(16). Although controversial, PrP-null mice are also found to be impaired in long term potentiation (17)(18)(19).…”

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confidence: 99%

Prion Protein Protects Human Neurons against Bax-mediated Apoptosis

Bounhar

Zhang

Goodyer

et al. 2001

Journal of Biological Chemistry

339

271

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The function of the cellular prion protein (PrP) is still poorly understood. We present here an unprecedented role for PrP against Bax-mediated neuronal apoptosis and show that PrP potently inhibits Bax-induced cell death in human primary neurons. Deletion of four octapeptide repeats of PrP (PrP⌬OR) and familial D178N and T183A PrP mutations completely or partially eliminate the neuroprotective effect of PrP. PrP remains anti-apoptotic despite truncation of the glycosylphosphatidylinositol (GPI) anchor signal peptide, indicating that the neuroprotective form of PrP does not require the abundant cell surface GPI-anchored PrP. Our results implicate PrP as a potent and novel anti-apoptotic protein against Bax-mediated cell death.Prion protein (PrP) 1 is a sialoglycoprotein that is highly expressed in brain, heart, lungs, and lymphoid system and at lower levels in several other tissues such as muscle (1, 2). Mature PrP contains two N-linked glycans and a disulfide bond (reviewed in Ref.3). PrP possesses a C-terminal GPI-anchoring signal and a transmembrane domain that can generate type I ( Ctm PrP) or type II ( Ntm PrP) transmembrane-spanning isoforms in isolated endoplasmic reticulum microsomes or phospholiposomes (4 -7). In most cells, the majority of the PrP localizes to the cell surface as a GPI-anchored protein (8). The complete translocation of PrP is dependent on translocation accessory factors (TrAF). In the absence of TrAF, PrP is exclusively synthesized in a transmembrane topology (7).Whereas the role of the infectious form of PrP in a number of human and animal neurodegenerative diseases has been extensively studied, the normal function of PrP is still poorly understood. PrP-null mice display no dramatic phenotype (9). However, evidence indicates that PrP may promote sleep continuity (10). PrP is involved in the regulation of presynaptic copper concentration, intracellular calcium concentration, activation of lymphocytes, astrocyte proliferation, and signal transduction and has antioxidant properties (11-16). Although controversial, PrP-null mice are also found to be impaired in long term potentiation (17)(18)(19). In addition, it has been shown that PrP-null neuronal cell lines are more susceptible to serum deprivation-induced cell death and that Bcl-2 overexpression can attenuate the sensitivity of PrP-null neuronal cell lines to serum deprivation (20). Kurschner and Morgan (21, 22) reported that yeast PrP fusion proteins interact with Bcl-2. Furthermore, four identical N-terminal PrP octapeptide repeats (OR) that are highly conserved in evolution share limited similarity with the Bcl-2 homology domain 2 (BH2) of Bcl-2 proteins (23, 24). Bcl-2 proteins are central to the regulation of cell death, and the BH2 domain is crucial to the anti-apoptotic function of Bcl-2 and its interaction with the pro-apoptotic Bax protein (24,25). Based on these features of PrP, we hypothesized that similar to Bcl-2 family members, PrP may play a role in the regulation of neuronal apoptosis. In the present study, we have...

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confidence: 99%

Prion Protein Protects Human Neurons against Bax-mediated Apoptosis

Bounhar

Zhang

Goodyer

et al. 2001

Journal of Biological Chemistry

339

271

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“…11 In vitro studies have demonstrated that a synthetic peptide corresponding to human PrP residues 106 -126 (PrP106 -126) is toxic to neurons, 12,13 with toxicity simultaneously dependent on PrP c expression, 12 the presence of microglia, 14 and possibly NMDA receptor-associated Ca 2ϩ channel activation. [15][16][17][18] Although the normal function of PrP c is unknown, a possible role for PrP in modulating neuronal oxidative stress has been recently identified. Studies using PrP Ϫ/Ϫ neuronal cultures have shown that a lack of PrP expression increases susceptibility to superoxide anions (O 2 Ϫ ) 14 or copper-mediated toxicity.…”

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confidence: 99%

Prion Protein-Deficient Neurons Reveal Lower Glutathione Reductase Activity and Increased Susceptibility to Hydrogen Peroxide Toxicity

White

Collins

Maher

et al. 1999

The American Journal of Pathology

181

103

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“…Also, in analogy with SOCCs modulation of transmitter release and synaptic plasticity in certain neurons (Emptage et al, 2001), PrP celicited Ca 2ϩ hotspots may recruit effectors in the immediate vicinity, e.g., Ca 2ϩ -activated K ϩ channels, thereby explaining why impairment of (Ca 2ϩ -dependent) K ϩ currents in PrP-null cells could not be attributed to specific alterations of voltage-gated Ca 2ϩ channels (Herms et al, 2000; but see Whatley et al, 1995). In the light of all these considerations, it is thus tempting to speculate that, as observed in the used cell model system, PrP c affects SOCC-dependent subplasma membrane Ca 2ϩ pools also in neurons.…”

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confidence: 99%