title: Proteomics analysis of amyloid and nonamyloid prion disease phenotypes reveals both common and divergent mechanisms of neuropathogenesis.
abstract: Prion diseases are a heterogeneous group of neurodegenerative disorders affecting various mammals including humans. Prion diseases are characterized by a misfolding of the host-encoded prion protein (PrP(C)) into a pathological isoform termed PrP(Sc). In wild-type mice, PrP(C) is attached to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor and PrP(Sc) typically accumulates in diffuse nonamyloid deposits with gray matter spongiosis. By contrast, when mice lacking the GPI anchor are infected with the same prion inoculum, PrP(Sc) accumulates in dense perivascular amyloid plaques with little or no gray matter spongiosis. In order to evaluate whether different host biochemical pathways were implicated in these two phenotypically distinct prion disease models, we utilized a proteomics approach. In both models, infected mice displayed evidence of a neuroinflammatory response and complement activation. Proteins involved in cell death and calcium homeostasis were also identified in both phenotypes. However, mitochondrial pathways of apoptosis were implicated only in the nonamyloid form, whereas metal binding and synaptic vesicle transport were more disrupted in the amyloid phenotype. Thus, following infection with a single prion strain, PrP(C) anchoring to the plasma membrane correlated not only with the type of PrP(Sc) deposition but also with unique biochemical pathways associated with pathogenesis.
authors.affiliation: Laboratory of Persistent Viral Diseases and ‡Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases , Hamilton, Montana 59840, United States.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Moore
authors.forename: Dan E
authors.initials: DE
authors.lastname: Sturdevant
authors.forename: Bruce
authors.initials: B
authors.lastname: Chesebro
authors.forename: Suzette A
authors.initials: SA
authors.lastname: Priola
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002853:Chromatography, Liquid; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D017096:Prion Diseases / Q000378:metabolism* / Q000503:physiopathology*; D040901:Proteomics / Q000379:methods*; D053719:Tandem Mass Spectrometry
chemical_list: D000682:Amyloid; D002118:Calcium
keywords: Alzheimer’s disease; LC−MS/MS; amyloid; cerebral amyloid angiopathy; glycosylphosphatidylinositol; prion disease; proteomics; transmissible spongiform encephalopathies