Prion precursor protein

The role of copper in other disease states is being investigated. For Alzheimer s disease studies, it has been found that the amyloid precursor protein interacts with copper to produce increased oxidant damage, and trace amounts of copper promote the precipitation of the amyloid p protein. In familial myotrophic lateral sclerosis about a quarter of the cases are caused by inherited dominant mutations in the Cu/Zn superoxide dismutase that probably result in abnormal Cu binding and the generation of reactive oxygen species. Copper has also been proposed to be involved in prion metabolism and fimction however, whether or not this imphcates copper in the prion diseases is unclear at this time. ... 

The cellular form of the prion protein, called PrP, is synthesized as a 253 amino acid precursor protein in humans (Figure 29. IB) (Prusiner, 1991). The N-terminal 22 amino acid residues serve as the signal peptide that allows insertion of the nascent PrP peptide into the secretory pathway during biosynthesis. The C-terminal 22 amino acid residues are involved in the covalent addition of the glycosylphosphatidylino-sitol (GPI) moiety to serine at amino acid 231 (i.e., Ser 9-The GPI anchor tethers PrP to the exhacellular side of the plasma membrane. PrP has two N-hnked glycosylation sites (Asn and Asn ) that are the sites of attachment of complex... 

Excursions too far into the realm of protein insolubility present a variety of tragic and ultimately fatal neurodegenerative diseases. In humans there are two causative proteins the prion protein of transmissible spongiform encephalopathies and the amyloid precursor protein of Alzheimer s disease. In general, there are some 15 proteins that by mutations or processing errors exhibit similar protein amyloid deposits that result in organ damage. Such protein insolubilities occur in mammals, birds, and even yeast. ... 

Alzheimer s, Parkinson s and prion diseases are characterized by neuronal loss and protein aggregates that may or may not be fibrillar. However, the exact identity of the neurotoxic species and the mechanism by which it kills neurons are unknown. Biophysical studies support the emerging notion that a prefibrillar oligomer (protofibril) may be responsible for cell death and that the fibrillar form that is typically observed post mortem may actually be neuroprotective. The laboratory of Peter Lansbury suggests that a subpopulation of the soluble protofibrils may function as pathogenic pores that might have the ability to permeabilize cell or mitochondrial membranes 35). Annular, pore-like structures are observed in familial mutants of a-synuclein (Parkinson s disease) and Alzheimer s precursor protein (Alzheimer s disease) as shown in Plate 3A 56). 

The normal cellular form of prion protein (PrPc) can exist as a Cu-metalloprotein in vivo (492). This PrPc is a precursor of the pathogenic protease-resistant form PrPsc, which is thought to cause scrapie, bovine spongiform encephalopathy (BSE), and Creutzfeldt—Jakob disease. Two octa-repeats of PHGGGWGQ have been proposed as Cu(II) binding sites centered on histidine (493). They lack secondary and tertiary structure in the absence of Cu(II). Neurons may therefore have special mechanisms to regulate the distribution of copper. 

Recently, high-pressure NMR measurements have enabled us to identify an intermediate conformer of the hamster prion protein, which has been suggested to be the PrP factor responsible for the PrP /PrP ° conversion or a closely related precursor. ... 

Steele AD, Emsley JG, Ozdinler PH, Lindquist S, Macklis JD (2006) Prion protein (PrPc) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis. Proc Natl Acad Sci USA 103 3416-3421. 

In order to reduce the complexity of the spectra acquired by precursor-ion analysis (m/z 204 as common product ion) in the analysis of complex glycan mixtures without prior LC separation, precursor-ion analysis was performed with larger ions, e.g., with common product ions like m/z 1935, 1406, and 1396 [70]. This method was applied in the characterization of over thirty complex A-linked glycan stmctures from the scrapie-associated prion protein PrP ". 

In 1986 a 54 kDa protein was identified under denaturing conditions that may act as a dimeric PrP precursor for the scrapie protein (Bendheim and Bolton, 1986). A 60 kDa form of a recombinant hamster prion protein was detected in murine neuroblastoma cells in 1995 (Priola et aL,... 

Rieger, R., Edenhofer, F, Lasmezas, C.I., and Weiss, S. (1997). The human 37-kDa laminin receptor precursor interacts with the prion protein in eukaryotic cells [see comments]. Nat. Med. 3, 1383-1388. 

Mobley WC, Nerve RL, Pmsiner SB, McKinley MP (1988) Nerve growth factor increases mRNA levels for the prion protein and the beta-amyloid protein precursor in developing hamster brain. Proc Natl Acad Sd USA 85 9811-9815... 

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