Clustering of sialylated glycosylphosphatidylinositol anchors mediates PrP-induced activation of cytoplasmic phospholipase A 2 and synapse damage.
Precisely how the accumulation of PrP (Sc) causes the neuronal degeneration that leads to the clinical symptoms of prion diseases is poorly understood. Our recent paper showed that the clustering of specific glycosylphosphatidylinositol (GPI) anchors attached to PrP proteins triggered synapse damage in cultured neurons. First, we demonstrated that small, soluble PrP (Sc) oligomers caused synapse damage via a GPI-dependent process. Our hypothesis, that the clustering of specific GPIs caused synapse damage, was supported by observations that cross-linkage of PrP (C), either chemically or by monoclonal antibodies, also triggered synapse damage. Synapse damage was preceded by an increase in the cholesterol content of synapses and activation of cytoplasmic phospholipase A 2 (cPLA 2). The presence of a terminal sialic acid moiety, a rare modification of mammalian GPI anchors, was essential in the activation of cPLA 2 and synapse damage induced by cross-linked PrP (C). We conclude that the sialic acid modifies local membrane microenvironments (rafts) surrounding clustered PrP molecules resulting in aberrant activation of cPLA 2 and synapse damage. A recent observation, that toxic amyloid-β assemblies cross-link PrP (C), suggests that synapse damage in prion and Alzheimer diseases is mediated via a common molecular mechanism, and raises the possibility that the pharmacological modification of GPI anchors might constitute a novel therapeutic approach to these diseases.
Department of Pathology and Infectious Diseases, Royal Veterinary College, Herts, UK. cbate@rvc.ac.uk
Clive
C
Bate
Alun
A
Williams
D000818:Animals; D004789:Enzyme Activation; D017261:Glycosylphosphatidylinositols / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism / Q000473:pathology; D019158:N-Acetylneuraminic Acid / Q000737:chemistry; D054467:Phospholipases A2 / Q000378:metabolism*; D018621:PrPC Proteins / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism / Q000473:pathology*; D013569:Synapses / Q000378:metabolism / Q000473:pathology*
D017261:Glycosylphosphatidylinositols; D018621:PrPC Proteins; D018620:PrPSc Proteins; D054467:Phospholipases A2; D019158:N-Acetylneuraminic Acid