Alterations in Ca<sup>2+</sup>-Buffering in Prion-Null Mice: Association with Reduced Afterhyperpolarizations in CA1 Hippocampal Neurons

Powell, Andrew D.; Toescu, Emil C.; Collinge, John; Jefferys, John G. R.

doi:10.1523/jneurosci.0675-08.2008

Cited by 30 publications

(23 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Surprisingly, engineered PrP C gene ablated (knockout) mice were initially reported as normal with no overt phenotypic abnormalities [5], which at the time suggested the prion protein could be functionally redundant. Subsequent studies, however, demonstrated various deficits and implicated PrP C in a diverse range of biological activities, with increasing evidence for roles in important cellular processes such as neuroprotection [6][7][8][9], cell signaling [10][11][12][13], neurological development and neuritogenesis [14,15], and synaptic function and plasticity [16][17][18][19][20]. Further, prion proteins from different mammalian species show high sequence identity, especially in the far C-terminus, with several post-translational modifications and structural features conserved across species [21][22][23][24][25], supporting the likely significant evolutionary and biological importance of this protein.…”

Section: Introductionmentioning

confidence: 99%

Prion protein “gamma-cleavage”: characterizing a novel endoproteolytic processing event

Lewis

Johanssen

Crouch

et al. 2015

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

The cellular prion protein (PrP C ) is a ubiquitously expressed protein of currently unresolved but potentially diverse function. Of putative relevance to normal biological activity, PrP C is recognized to undergo both a-and b-endoproteolysis, producing the cleavage fragment pairs N1/C1 and N2/C2, respectively. Experimental evidence suggests the likelihood that these processing events serve differing cellular needs. Through the engineering of a C-terminal c-myc tag onto murine PrP C , as well as the selective use of a far-Cterminal anti-PrP antibody, we have identified a new PrP C fragment, nominally 'C3', and elaborating existing nomenclature, 'c-cleavage' as the responsible proteolysis. Our studies indicate that this novel c-cleavage event can occur during transit through the secretory pathway after exiting the endoplasmic reticulum, and after PrP C has reached the cell surface, by a matrix metalloprotease.We found that C3 is GPI-anchored like other C-terminal and full length PrP C species, though it does not localize primarily at the cell surface, and is preferentially cleaved from an unglycosylated substrate. Importantly, we observed that C3 exists in diverse cell types as well as mouse and human brain tissue, and of possible pathogenic significance, c-cleavage may increase in human prion diseases. Given the likely relevance of PrP C processing to both its normal function, and susceptibility to prion disease, the potential importance of this previously underappreciated and overlooked cleavage event warrants further consideration.

show abstract

Section: Introductionmentioning

confidence: 99%

Prion protein “gamma-cleavage”: characterizing a novel endoproteolytic processing event

Lewis

Johanssen

Crouch

et al. 2015

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…Although the role of calcium in the initiation of tooth tissue cell differentiation is not well defined, the location of PrP at the apical border of both secretory ameloblasts and odontoblasts is consis- tent with the hypothesis that this protein is related to Ca 2+ transport (Fuhrmann et al, 2006), or regulating Ca 2+ homeostasis (Powell et al, 2008).…”

Section: Discussionmentioning

confidence: 93%

Multiple effects of the cellular prion protein on tooth development

Zhang

Kim²,

Opsahl-Vital³

et al. 2011

Int. J. Dev. Biol.

View full text Add to dashboard Cite

The role of the prion protein (PrP) in transmissible spongiform encephalopathies has been the focus of intense investigation. However, less is known about the physiological function of normal cellular PrP (PrP C ). In adult human teeth, PrP C has been identified in odontoblasts, cementoblasts and epithelial remnants of Malassez. In this study, we have localized PrP C in developing human and mouse teeth, and investigated the function of PrP using a PrP-knockout (Prnp 0/0 ) mouse model. PrP C was detected in developing human and mouse ameloblasts and odontoblasts. In vitro, undifferentiated dental mesenchymal cells from embryonic day 18 (E18) Prnp 0/0 mouse molars proliferated much more rapidly compared to age-matched, wild-type (wt) mouse molar dental mesenchymal cells. Histochemistry and immunohistochemical analyses showed a subtle but measurable phenotype, with the absence of PrP resulting in earlier initiation of both dentin and enamel formation. Consistent with this finding, laser microdissected odontoblasts from newborn Prnp 0/0 mouse incisors had a reduced proliferation rate, as measured by the expression of proliferating cell nuclear antigen (PCNA), and increased type 1 collagen mRNA expression. Dentin microhardness of the fully erupted molars was reduced and incisal enamel mineralization was delayed in Prnp 0/0 compared to age-matched wt mouse teeth. Taken together, these results suggest that PrP C affects multiple processes involved in tooth formation, through regulating the differentiation of ameloblasts and odontoblasts.

show abstract

“…Recombinant PrP was also demonstrated to modulate voltage-sensitive calcium channels in primary cerebellar granule cells [102]. A few years later, the initial hypothesis was revisited by Powell et al [103], who explained the differences in calcium homeostasis seen in PrP C -deficient mice as a consequence of calcium buffering in the endoplasmic reticulum (ER). Lazzari et al [104] described a dramatic increase of cytosolic calcium in PrP C -deficient granule neurons due to lower expression of PMCA and SERCA, the two major calcium-extruding pumps respectively located on the cell membrane and the ER.…”

Section: Prion Protein and Calcium Signalingmentioning

confidence: 99%

Prion protein and its role in signal transduction

Didonna

2013

Cellular and Molecular Biology Letters

View full text Add to dashboard Cite

Prion diseases are a class of fatal neurodegenerative disorders that can be sporadic, genetic or iatrogenic. They are characterized by the unique nature of their etiologic agent: prions (PrP Sc ). A prion is an infectious protein with the ability to convert the host-encoded cellular prion protein (PrP C ) into new prion molecules by acting as a template. Since Stanley B. Prusiner proposed the "protein-only" hypothesis for the first time, considerable effort has been put into defining the role played by PrP C in neurons. However, its physiological function remains unclear. This review summarizes the major findings that support the involvement of PrP C in signal transduction.

show abstract

Alterations in Ca²⁺-Buffering in Prion-Null Mice: Association with Reduced Afterhyperpolarizations in CA1 Hippocampal Neurons

Cited by 30 publications

References 48 publications

Prion protein “gamma-cleavage”: characterizing a novel endoproteolytic processing event

Prion protein “gamma-cleavage”: characterizing a novel endoproteolytic processing event

Multiple effects of the cellular prion protein on tooth development

Prion protein and its role in signal transduction

Contact Info

Product

Resources

About

Alterations in Ca2+-Buffering in Prion-Null Mice: Association with Reduced Afterhyperpolarizations in CA1 Hippocampal Neurons

Cited by 30 publications

References 48 publications

Prion protein “gamma-cleavage”: characterizing a novel endoproteolytic processing event

Prion protein “gamma-cleavage”: characterizing a novel endoproteolytic processing event

Multiple effects of the cellular prion protein on tooth development

Prion protein and its role in signal transduction

Contact Info

Product

Resources

About

Alterations in Ca²⁺-Buffering in Prion-Null Mice: Association with Reduced Afterhyperpolarizations in CA1 Hippocampal Neurons