Copper binding is the governing determinant of prion protein turnover

Haigh, Cathryn L.; Edwards, Kate M.; Brown, David R.

doi:10.1016/j.mcn.2005.07.001

Cited by 50 publications

(54 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, there is recent evidence for MAPK activation by signaling endosomes [15]. PrP C is internalized in response to copper [46], and this reaction requires the octameric repeat domain and the palindromic sequence starting at the N1/C1 cleavage site to be intact [47,48]. Signaling endosomes have been especially associated with clathrin and dynamin mediated internalization [15,49,50], and these are both pathways with which PrP C has been shown to interact [51,52]; hence, the role of copper in these reactions may be to promote the internalization of PrP C to facilitate engagement with signaling intermediates.…”

Section: Discussionmentioning

confidence: 99%

PrPC-related signal transduction is influenced by copper, membrane integrity and the alpha cleavage site

et al. 2009

View full text Add to dashboard Cite

The copper-binding, membrane-anchored, cellular prion protein (PrP C ) has two constitutive cleavage sites producing distinct N-and C-terminal fragments (N1/C1 and N2/C2). Using RK13 cells expressing either human PrP C , mouse PrP C or mouse PrP C carrying the 3F4 epitope, this study explored the influence of the PrP C primary sequence on endoproteolytic cleavage and one putative PrP C function, MAP kinase signal transduction, in response to exogenous copper with or without a perturbed membrane environment. PrP C primary sequence, especially that around the N1/C1 cleavage site, appeared to influence basal levels of proteolysis at this location and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, with increased processing demonstrating an inverse relationship with basal ERK1/2 activation. Human PrP C showed increased N1/C1 cleavage in response to copper alone, accompanied by specific p38 and JNK/SAPK phosphorylation. Combined exposure to copper plus the cholesterol-sequestering antibiotic filipin resulted in a mouse PrP C -specific substantial increase in signal protein phosphorylation, accompanied by an increase in N1/C1 cleavage. Mouse PrP C harboring the human N1/C1 cleavage site assumed more human-like profiles basally and in response to copper and altered membrane environments. Our results demonstrate that the PrP C primary sequence around the N1/C1 cleavage site influences endoproteolytic processing at this location, which appears linked to MAP kinase signal transduction both basally and in response to copper. Further, the primary sequence appears to confer a mutual dependence of N1/C1 cleavage and membrane integrity on the fidelity of PrP C -related signal transduction in response to exogenous stimuli. IntroductionCumulative experimental evidence supports that abnormal isomers of the prion protein constitute the causative agent in transmissible spongiform encephalopathies (TSEs, also known as prion diseases) [1,2], with neuronal expression and membrane anchorage of wild-type PrP being essential for efficient pathogenesis [3][4][5][6][7][8][9]. The disease-associated conformer, termed PrP Sc , is a structurally altered form of the normal cellular protein, PrP C . PrP C is a glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein, which has been shown to bind copper within an N-terminal octameric repeat region and also at one or more sites slightly more C-terminal of the repeat region [10][11][12][13].Despite much investigation and characterization of the properties of PrP C and PrP Sc , the primary function of PrP C and the principal pathogenic pathways of TSEs remain unresolved. One suggested role for PrP C is the transduction of signals from the external environment into the cell interior, a function circumstantially supported by the localization of PrP C within plasma membrane detergentresistant microdomains (also known as lipid rafts), which are now widely recognized as membrane-signaling plat-forms [14]. The plasma membrane constitutes a critical site for the activatio...

show abstract

Section: Discussionmentioning

confidence: 99%

PrPC-related signal transduction is influenced by copper, membrane integrity and the alpha cleavage site

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Interestingly, at the synaptic cleft, Cu 2+ regulation by binding to PrP c has been associated with the regulation of redox levels to facilitate neural transmission (Brown et al, 1997a;Herms et al, 1999). However, PrP c functions appear to be more diverse than a single redox control by PrP c -Cu 2+ binding in the cell or in the synapse, since PrP c -Cu 2+ in vitro binding promotes clathrin-mediated endocytosis (Cheng et al, 2006;Haigh et al, 2005;Pauly and Harris, 1998). This observation suggests that PrP c or PrP c -Cu 2+ binding is involved in the turnover of several receptors at the plasma membrane.…”

Section: Prp C Andmentioning

confidence: 99%

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

Nicolas

Gavı́n

Rı́o

2009

Brain Research Reviews

View full text Add to dashboard Cite

show abstract

“…SMB cells were transfected with a plasmid (pEGFP) expressing mouse PrP as a fusion with GFP. Previous studies have shown that PrP expressed with this tagged is transported to and from the surface in a way that is identical to that of untagged PrP (26). SMB cells expressing GFP-PrP were treated with 10 M of the Congo red derivatives.…”

Section: Discussionmentioning

confidence: 99%

“…Two of these constructs expressed the whole mouse PrP open reading frame. The first of these was pCDNA3.1 (Invitrogen), with the PrP open reading frame cloned between the HindIII and EcoR1 sites of the multiple cloning site and green fluorescent protein (GFP)-PrP as previously described (26). The latter construct is based on pEGFP (Invitrogen), but the GFP gene was cloned between codons 37 and 38 of the PrP open reading frame.…”

Section: Methodsmentioning

confidence: 99%

“…We used a GFP-tagged PrP system to look at the levels of PrP expression at the cell surface in SMB infected cells. Following treatment of the cells, the level of GFP signal was monitored for 2 h. This period of time was chosen because compounds that alter the rate of PrP internalization have been shown to be effective in this time range (26). None of the Congo red compounds tested had any effect on GFP-tagged PrP expression levels at the cell surface (Fig.…”

Section: Localization Of Prpmentioning

confidence: 99%

See 1 more Smart Citation

Mechanistic Insights into the Cure of Prion Disease by Novel Antiprion Compounds

Webb

Lekishvili

Loeschner

et al. 2007

J Virol

Self Cite

View full text Add to dashboard Cite

Prion diseases are fatal neurodegenerative disorders. Identification of possible therapeutic tools is important in the search for a potential treatment for these diseases. Congo red is an azo dye that has been used for many years to detect abnormal prion protein in the brains of diseased patients or animals. Congo red has little therapeutic potential for the treatment of these diseases due to toxicity and poor permeation of the blood-brain barrier. We have prepared two Congo red derivatives, designed without these liabilities, with potent activity in cellular models of prion disease. One of these compounds cured cells of the transmissible agent. The mechanism of action of these compounds is possibly multifactorial. The high affinity of Congo red derivatives, including compounds that are ineffective and are effective at the cure of prion disease, for abnormally folded prion protein suggests that the amyloidophylic property of these derivatives is not as critical to the mechanism of action as other effects. Congo red derivatives that are effective at the cure of prion disease increased the degradation of abnormal PrP by the proteasome. Therefore, the principal mechanism of action of the Congo red analogues was to prevent inhibition of proteasomal activity by PrP Sc .

show abstract

Copper binding is the governing determinant of prion protein turnover

Cited by 50 publications

References 50 publications

PrPC-related signal transduction is influenced by copper, membrane integrity and the alpha cleavage site

PrPC-related signal transduction is influenced by copper, membrane integrity and the alpha cleavage site

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

Mechanistic Insights into the Cure of Prion Disease by Novel Antiprion Compounds

Contact Info

Product

Resources

About