title: Neurodegeneration induced by clustering of sialylated glycosylphosphatidylinositols of prion proteins.
abstract: The transmissible spongiform encephalopathies, more commonly known as the prion diseases, are associated with the production and aggregation of disease-related isoforms of the prion protein (PrP(Sc)). The mechanisms by which PrP(Sc) accumulation causes neurodegeneration in these diseases are poorly understood. In cultured neurons, the addition of PrP(Sc) alters cell membranes, increasing cholesterol, activating cytoplasmic phospholipase A(2) (cPLA(2)), and triggering synapse damage. These effects of PrP(Sc) are dependent upon its glycosylphosphatidylinositol (GPI) anchor, suggesting that it is the increased density of GPIs that occurs following the aggregation of PrP(Sc) molecules that triggers neurodegeneration. This hypothesis was supported by observations that cross-linkage of the normal cellular prion protein (PrP(C)) also increased membrane cholesterol, activated cPLA(2), and triggered synapse damage. These effects were not seen after cross-linkage of Thy-1, another GPI-anchored protein, and were dependent on the GPI anchor attached to PrP(C) containing two acyl chains and sialic acid. We propose that the aggregation of PrP(Sc), or the cross-linkage of PrP(C), causes the clustering of sialic acid-containing GPI anchors at high densities, resulting in altered membrane composition, the pathological activation of cPLA(2), and synapse damage.
authors.affiliation: Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire AL9 7TA, United Kingdom. cbate@rvc.ac.uk
authors.forename: Clive
authors.initials: C
authors.lastname: Bate
authors.forename: Alun
authors.initials: A
authors.lastname: Williams
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism*; D017261:Glycosylphosphatidylinositols / Q000235:genetics / Q000378:metabolism*; D054513:Group IV Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019158:N-Acetylneuraminic Acid / Q000235:genetics / Q000378:metabolism*; D018620:PrPSc Proteins / Q000235:genetics / Q000378:metabolism*; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013569:Synapses / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018800:Thy-1 Antigens / Q000235:genetics / Q000378:metabolism
chemical_list: D058851:GPI-Linked Proteins; D017261:Glycosylphosphatidylinositols; D018620:PrPSc Proteins; D018800:Thy-1 Antigens; D002784:Cholesterol; D054513:Group IV Phospholipases A2; D019158:N-Acetylneuraminic Acid