Three scrapie prion isolates exhibit different accumulation patterns of the prion protein scrapie isoform.

Abstract

To investigate the molecular basis of prion diversity, we inoculated transgenic mice expressing the Syrian hamster prion protein (PrP) with three distinct prion isolates. We compared the three isolates designated Sc237, 139H, and Me7H in Tg(SHaPrP)7 mice with clinical signs of scrapie because the incubation times with these mice are considerably shorter than the times found with hamsters. Each prion isolate produced a distinctive pattern of the scrapie isoform of PrP (PrPsc) accumulation, as determined by histoblotting, a technique developed for the regional mapping of PrPsc deposition.The PrPsc pattern with the Me7H isolate was particularly interesting because it appeared to be confined to the hypothalamus and related structures-including the interstitial nucleus of the stria terminalis, the paraventricular nucleus of the thalamus, and periaqueductal grey. Additionally, the regions of PrPsc accumulation remained highly restricted, even though the incubation time for Me7H scrapie was significantiy longer than with Sc237 and 139H isolates. Neuropathological changes characterized by neuronal vacuolation and astrocytic gliosis were confined to those regions where PrPsc accumulated. These findings argue that the cell-speciffc propagation of prion isolates may be responsible for different properties exhibited by each of the isolates.

Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins.

“…This assertion is supported by the finding that ablation of the PrP gene is apparently not deleterious to mice; thus, the prion diseases appear to be the result of PrPSc accumulation rather than a PrPc deficiency (39). PrPsc accumulation is restricted to specific regions of the central nervous system and it is only these regions which exhibit vacuolation and reactive gliosis (10,(40)(41)(42). The foregoing findings lend further support to the argument that prion diseases are disorders of protein conformation.…”

“…While a-helical -, psheet transitions feature in the formation of PrPSc and thus seem to be the fundamental events underlying prion "infection," the existence of scrapie "strains" remains perplexing (60). Prion "strains" produce distinct patterns of PrPSc deposition in the brain and often have different incubation times (40)(41)(42). In the continuing absence of any scrapie-specific nucleic acid, the profound conformational changes which PrPC undergoes during its conversion to PrPSc raise the possibility that the information carried in prion "strains" resides within the conformation of PrPsc (1).…”

Prominent pancreatic endocrinopathy and altered control of food intake disrupt energy homeostasis in prion diseases

“…within tissues and the resulting effects on cellular function remains elusive. Nevertheless, prion-strain-specific targeting of the hypothalamus has been shown at clinical disease in both hamster and mouse models of prion disease (DeArmond et al 1993). In one study (Carp et al 1984), scrapie strains that induced obesity in mice (e.g., ME7 and 22L) also caused intense vacuolation and lesions within the hypothalamus compared with strains that did not cause obesity (e.g., 22A).…”

“…Evidence from both natural and experimental prion diseases suggest that peripheral endocrine glands (Ye & Carp 1995, 1996, Sigurdson et al 2001, the hypothalamus (DeArmond et al 1993), and the brain (Sigurdson et al 2001) demonstrate varying degrees of PrP Sc deposition and/or disease-related pathology by the time neurological symptoms have progressed. However, the spatiotemporal relationship between sites of prion infection and altered endocrine homeostasis has not been established.…”

Molecular characterization of proteolytic cleavage sites of the Pseudomonas syringae effector AvrRpt2

“…Strains or varieties of prions have been defined by incubation times and the distribution of neuronal vacuolation (215,265). Subsequently, the patterns of PrP Sc deposition were found to correlate with vacuolation profiles, and these patterns were also used to characterize strains of prions (231,266,267).…”