The Neurochemistry of Prion Diseases

DeArmond, Stephen J.; Prusiner, Stanley B.

doi:10.1111/j.1471-4159.1993.tb09792.x

Cited by 38 publications

(13 citation statements)

References 79 publications

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“…It is of interest to note that none of the drugs completely inhibited PLA 2 activity, possibly because there exist several distinct enzymes with PLA 2 activity including cytosolic (cPLA 2 ) and secretory (sPLA 2 ) isozymes (19). Although aristolochic acid and CDP inhibit both cPLA 2 and sPLA 2 , low concentrations of AACOCF 3 or BEL, which are reported to selectively inhibit cPLA 2 (20), inhibited PrP res formation (Table I) indicating that cPLA 2 may be the isozyme of interest.…”

Section: Discussionmentioning

confidence: 99%

“…These observations raise the possibility that the activation of PLA 2 seen in prion infected cells and the production of PAF may encourage the formation of PrP res by enhancing propitious trafficking and sorting pathways. In some cell lines PAF antagonists prevent endocytosis (39), while in other studies, cPLA 2 inhibitors (AA-COCF 3 or BEL) prevent the maintenance of the Golgi network (40), endosome fusion, and endocytosis (41), and modulate the intracellular trafficking of some proteins (42). Together with the observation that the Golgi and the endosomal compartments are involved in the trafficking of a GFP-tagged PrP C (43), these observations suggest that treatment of neurons with PLA 2 inhibitors or PAF antagonists may inhibit PrP res formation by altering the intracellular trafficking of PrP C .…”

Section: Discussionmentioning

confidence: 99%

“…Drugs-Dexamethasone, prednisolone, prednisone, hydrocortisone, ibuprofen, acetyl salicylic acid, nordihydroguaiaretic acid (NDGA), AA-COCF 3 , aristolochic acid, bromoenol lactone (BEL), and neomycin sulfate were obtained from Sigma. Cytidine-5-diphosphocholine (CDP), caffeic acid, 1-O-alkyl-2-acetyl-sn-glycerol-3-phosphocholine (PAF), and 1-O-alkyl-2-acetyl-sn-glycerol-3-phospho-(N,N,N-trimethyl)-hexanolamine (hexa-PAF) were obtained from Novabiochem (Nottingham, UK).…”

Section: Methodsmentioning

confidence: 99%

“…The formation of PrP Sc is accompanied by changes in biological and biochemical properties such as an increased resistance to proteases (2), the protease-resistant core of PrP Sc designated PrP res . This PrP Sc self-aggregates and forms amyloidgenic fibrils and, in most prion diseases, aggregates of PrP Sc are detected in the diseased brain before neuronal loss is observed (3).…”

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confidence: 99%

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Phospholipase A2 Inhibitors or Platelet-activating Factor Antagonists Prevent Prion Replication

Bate

Reid

Williams

2004

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Phospholipase A2 Inhibitors or Platelet-activating Factor Antagonists Prevent Prion Replication

Bate

Reid

Williams

2004

Journal of Biological Chemistry

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“…These diseases involve partial unfolding of the monomeric, cellular prion protein (PrP C ) and its subsequent misfolding to the scrapie isoform (generically denoted here as PrP Sc ). The latter form can, but does not always, aggregate to form amyloid plaques in the brain (4). Whereas the structure of fragments of hamster, mouse, bovine, and human PrP C have been well characterized by NMR (5-9), high resolution structures of PrP Sc aggregates remain elusive.…”

mentioning

confidence: 99%

From conversion to aggregation: Protofibril formation of the prion protein

DeMarco

Daggett

2004

Proc. Natl. Acad. Sci. U.S.A.

295

294

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The ability to diagnose and treat prion diseases is limited by our current understanding of the conversion process of the protein from healthy to harmful isoform. Whereas the monomeric, benign species is well characterized, the misfolded conformations responsible for infectivity and neurodegeneration remain elusive. There is mounting evidence that fibrillization intermediates, or protofibrils, but not mature fibrils or plaques, are the pathogenic species in amyloid diseases. Here, we use molecular dynamics to simulate the conversion of the prion protein. Molecular dynamics simulation produces a scrapie prion protein-like conformation enriched in ␤-structure that is in good agreement with available experimental data. The converted conformation was then used to model a protofibril by means of the docking of hydrophobic patches of the template structure to form hydrogen-bonded sheets spanning adjacent subunits. The resulting protofibril model provides a nonbranching aggregate with a 31 axis of symmetry that is in good agreement with a wide variety of experimental data; importantly, it was derived from realistic simulation of the conversion process.

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Prion-Protein-Specific Aptamer Reduces PrPSc Formation

Proske¹,

Gilch²,

Wopfner³

et al. 2002

ChemBioChem

141

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The critical initial event in the pathophysiology of transmissible spongiform encephalopathies (TSEs) appears to be the conversion of the cellular prion protein (PrP C ) into the abnormal isoform PrP Sc . This isoform forms high-molecular-weight protease K (PK) resistant aggregates that accumulate in the central nervous system of affected individuals. We have selected nuclease-resistant 2'-amino-2'-deoxypyrimidine-modified RNA aptamers which recognize a peptide comprising amino acid residues 90 ± 129 of the human prion protein with high specificity. This domain of prion proteins is thought to be functionally important for the conversion of PrP C into its pathogenic isoform PrP Sc and is highly homologous among prion proteins of various species including mouse, hamster, and man. Consequently, aptamer DP7 binds to the full-length human, mouse, and hamster prion protein. At low concentrations in the growth medium of persistently prion-infected neuroblastoma cells, aptamer DP7 significantly reduced the relative proportion of de novo synthesized PK-resistant PrP Sc within only 16 h. These findings may open the door towards a rational development of a new class of drugs for the therapy or prophylaxis of prion diseases.

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The Neurochemistry of Prion Diseases

Cited by 38 publications

References 79 publications

Phospholipase A2 Inhibitors or Platelet-activating Factor Antagonists Prevent Prion Replication

Phospholipase A2 Inhibitors or Platelet-activating Factor Antagonists Prevent Prion Replication

From conversion to aggregation: Protofibril formation of the prion protein

Prion-Protein-Specific Aptamer Reduces PrPSc Formation

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