Prion protein with an E200K mutation displays properties similar to those of the cellular isoform PrP(C).

Creutzfeldt-Jakob disease (CJD) in Libyan Jews, linked to the E200K mutation in PRNP (E200KCJD), is the most prevalent of the inherited prion diseases. As other prion diseases, E200KCJD is characterized by the brain accumulation of PrP(Sc), a pathologic conformational isoform of a normal glycoprotein denominated PrP(C). To investigate whether the E200K mutation is enough to de novo confer PrP(Sc) properties to mutant PrP, as suggested by experiments in Chinese hamster ovary cells, we examined the biochemical behavior of E200KPrP in brains and fibroblasts from sporadic as well as homozygous and heterozygous E200KCJD patients, asymptomatic transgenic mice carrying the E200K mutation, as well as in normal and scrapie-infected mouse neuroblastoma cells expressing E200KPrP.

Reconstitution of prion infectivity from solubilized protease-resistant PrP and nonprotein components of prion rods.

The scrapie isoform of the prion protein, PrP(Sc), is the only identified component of the infectious prion, an agent causing neurodegenerative diseases such as Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Following proteolysis, PrP(Sc) is trimmed to a fragment designated PrP 27-30. Both PrP(Sc) and PrP 27-30 molecules tend to aggregate and precipitate as amyloid rods when membranes from prion-infected brain are extracted with detergents.

The cellular prion protein colocalizes with the dystroglycan complex in the brain.

The function of PrP(C), the cellular prion protein (PrP), is still unknown. Like other glycophosphatidylinositol-anchored proteins, PrP resides on Triton-insoluble, cholesterol-rich membranous microdomains, termed rafts. We have recently shown that the activity and subcellular localization of the neuronal isoform of nitric oxide synthase (nNOS) are impaired in adult PrP(0/0) mice as well as in scrapie-infected mice.

Effects of adrenalectomy and corticosterone replacement on the hypothalamic-pituitary response to neural stimuli.

In this study we examined whether circulating glucocorticoids (GC) have a permissive facilitatory role in the hypothalamo-pituitary-adrenal (HPA) axis responses to neural or metabolic stimuli. In control sham operated rats the exposure to photic or acoustic neural stimuli and to either cytoglucopenia induced by 2-deoxyglucose (2-DG) or to hypoglycemia induced by insulin caused a significant 5-fold increase in serum ACTH as compared to basal non-stress levels. In adrenalectomized (Adex) rats tested under basal conditions at 4, 7 and 14 days post-Adex, serum ACTH gradually increased in a time-dependent manner, Also, at 4 days post-Adex the median eminence (ME) content of CRH-41 was markedly depleted but gradually recovered to control levels at 7 and 14 days post-Adex.

Effects of adrenergic and serotonergic agonists in the amygdala on the hypothalamo-pituitary-adrenocortical axis.

The effect of direct administration of adrenergic and serotonergic (5-HT) agonists into the central nucleus of the amygdala (AMG) on the hypothalamo-pituitary-adrenal (HPA) axis have been studied in intact male rats and in animals with 6-hydroxydopamine (6-OHDA) or 5, 7-dihydroxytryptamine (5,7-DHT) neurotoxic lesions in the paraventricular nucleus of the hypothalamus (PVN). In intact animals, the administration of phenylephrine, an alpha1 adrenergic agonist or 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) a 5-HT(1A) agonist caused depletion of median eminence corticotropin releasing hormone and a rise in serum adrenocorticotrophic hormone (ACTH) and corticosterone (CS) levels. Isoproterenol a beta agonist was more effective than phenylephrine and a 5-HT(1B) agonist CP-93, 129 was less effective than 8-OH-DPAT on the adrenocortical activity.