A dementing illness associated with a novel insertion in the prion protein gene

Owen, F.; Poulter, Mark; Collinge, John; Leach, M.; Lofthouse, R.; Crow, Timothy J.; Harding, A. E.

doi:10.1016/0169-328x(92)90056-h

Cited by 85 publications

(47 citation statements)

References 11 publications

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“…In light of the results reported here, these findings could also be explained by altered intracellular trafficking of the mutated PrP because of the alterations in the N-terminal part. Clinical studies have shown that two to nine octapeptides in addition to the normal five segregate with familial forms of Creutzfeldt-Jakob disease (46,47) and nontransmissible prion disease in transgenic mice (48). Studies addressing the effect of these mutations on subcellular trafficking are in progress.…”

Section: Progressive Deletions Within the N Terminus Of Prp C Results mentioning

confidence: 99%

Essential Role of the Prion Protein N Terminus in Subcellular Trafficking and Half-life of Cellular Prion Protein

Nunziante

Gilch

Schätzl

2003

Journal of Biological Chemistry

103

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Section: Progressive Deletions Within the N Terminus Of Prp C Results mentioning

confidence: 99%

Essential Role of the Prion Protein N Terminus in Subcellular Trafficking and Half-life of Cellular Prion Protein

Nunziante

Gilch

Schätzl

2003

Journal of Biological Chemistry

103

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“…In order to determine whether PrP was constitutively shed by means of a specific enzymic mechanism and not through a nonspecific process such as membrane blebbing, we compared the shedding of wt-PrP to that of PrP-DA and PrP- PG14. PrP-DA possesses an additional membrane anchoring domain at the N terminus (30), and PrP-PG14 is the mouse PrP homologue of a nine-octapeptide insertional mutation, which is associated with an inherited form of Creutzfeldt-Jakob disease in humans (37)(38)(39). PrP-PG14 is known to be resistant to PI-PLC cleavage (40), implying that the addition of the nine octapeptide repeats imparts an additional form of membrane interaction to the protein.…”

Section: Discussionmentioning

confidence: 99%

Dual Mechanisms for Shedding of the Cellular Prion Protein

Parkin

Watt

Turner

et al. 2004

Journal of Biological Chemistry

125

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The cellular prion protein (PrP C ) is essential for the pathogenesis and transmission of prion diseases. Whereas the majority of PrP C is bound to the cell membrane via a glycosylphosphatidylinositol (GPI) anchor, a secreted form of the protein has been identified. Here we show that PrP C can be shed into the medium of human neuroblastoma SH-SY5Y cells by both proteaseand phospholipase-mediated mechanisms. The constitutive shedding of PrP C was inhibited by a range of hydroxamate-based zinc metalloprotease inhibitors in a manner identical to the ␣-secretase-mediated shedding of the amyloid precursor protein, indicating a proteolytic shedding mechanism. Like amyloid precursor protein, this zinc metalloprotease-mediated shedding of PrP C could be stimulated by phorbol myristate acetate and by copper ions. The lipid raft-disrupting agents filipin and methyl-␤-cyclodextrin promoted the shedding of PrP C via a distinct mechanism that was not inhibited by hydroxamate-based inhibitors. Filipin-mediated shedding of PrP C is likely to occur via phospholipase cleavage of the GPI anchor, since a transmembrane polypeptide-anchored PrP construct was not shed in response to filipin treatment. Collectively, our data indicate that shedding of PrP C can occur via both secretase-like proteolytic cleavage of the protein and phospholipase cleavage of the GPI anchor moiety.

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“…Additional octarepeats have been identified in patients suffering from familial CJD (Owen et al, 1990(Owen et al, , 1992Goldfarb et al, 1991Goldfarb et al, , 1993Campbell et al, 1996). PrP encompassing nine additional octarepeats associated with familial CJD failed to undergo Cu 2 + -mediated endocytosis, suggesting that neurodegeneration may arise from the ablation of internalization due to mutation of the octarepeats (Sumudhu et al, 2001).…”

Section: Influence Of Additional Octarepeats In the Prp/prp Interactimentioning

confidence: 99%

“…A series of mutations affect the octarepeat region of the prion protein. fCJD patients encompassing two (Goldfarb et al, 1993), four (Campbell et al, 1996), five (Goldfarb et al, 1991), six (Owen et al, 1990), seven (Goldfarb et al, 1991), eight (Goldfarb et al, 1991) and nine additional octarepeats (Owen et al, 1992) have been described. All these patients are heterozygous regarding these mutations (Majtenyi et al, 2000).…”

Section: Introductionmentioning

confidence: 99%