No abstract

Objective: To report a novel prion disease characterized by distinct histopathological and immunostaining features, and associated with an abnormal isoform of the prion protein (PrP) that, contrary to the common prion diseases, is predominantly sensitive to protease digestion. Methods: Eleven subjects were investigated at the National Prion Disease Pathology Surveillance Center for clinical, histopathological, immunohistochemical, genotypical, and PrP characteristics. Results: Patients presented with behavioral and psychiatric manifestations on average at 62 years, whereas mean disease duration was 20 months. The type of spongiform degeneration, the PrP immunostaining pattern, and the presence of microplaques distinguished these cases from those with known prion diseases. Typical protease-resistant PrP was undetectable in the cerebral neocortex with standard diagnostic procedures. After enrichment, abnormal PrP was detected at concentrations 16 times lower than common prion diseases; it included nearly 4 times less protease-resistant PrP, which formed a distinct electrophoretic profile. The subjects examined comprised about 3% of sporadic cases evaluated by the National Prion Disease Pathology Surveillance Center. Although several subjects had family histories of dementia, no mutations were found in the PrP gene open reading frame. Interpretation: The distinct histopathological, PrP immunohistochemical, and physicochemical features, together with the homogeneous genotype, indicate that this is a previously unidentified type of disease involving the PrP, which we designated "protease-sensitive prionopathy" (or PSPr). Protease-sensitive prionopathy is not rare among prion diseases, and it may be even more prevalent than our data indicate because protease-sensitive prionopathy cases are likely also to be classified within the group of non-Alzheimer's dementias.

Summary Prions are unconventional infectious agents composed exclusively by the misfolded prion protein (PrPSc), which transmits the disease by propagating its abnormal conformation to the cellular prion protein (PrPC). A key characteristic of prions is their species barrier, by which prions from one species can only infect a limited number of other species. Here we report the generation of novel infectious prions by inter-species transmission of PrPSc misfolding in vitro. Hamster PrPC misfolded by mixing with mouse PrPSc generated new prions that were infectious to wild type hamsters. Similarly, new mouse prions were generated by crossing the species barrier in the opposite direction. A detailed characterization of the infectious, biochemical and histological properties of the disease produced indicate that the in vitro generated material across the species barrier correspond to new prion strains. Successive rounds of PMCA amplification result in a progressive adaptation of the in vitro produced prions, in a process reminiscent to the strain stabilization process observed upon serial passage in vivo. Our results indicate that PMCA is a valuable tool to investigate cross-species transmission and suggest that species barrier and strain generation are determined by the propagation of PrP misfolding.

The unfolded protein response (UPR) is a conserved adaptive reaction that increases cell survival under endoplasmic reticulum (ER) stress conditions. X-box-binding protein-1 (XBP-1) is a key transcriptional regulator of the UPR that activates genes involved in protein folding, secretion, and degradation to restore ER function. The occurrence of chronic ER stress has been extensively described in neurodegenerative conditions linked to protein misfolding and aggregation. However, the role of the UPR in the CNS has not been addressed directly. Here we describe the generation of a brain-specific XBP-1 conditional KO strain (XBP-1 Nes−/− ). XBP-1 Nes−/− mice are viable and do not develop any spontaneous neurological dysfunction, although ER stress signaling in XBP-1 Nes−/− primary neuronal cell cultures was impaired. To assess the function of XBP-1 in pathological conditions involving protein misfolding and ER stress, we infected XBP-1 Nes−/− mice with murine prions. To our surprise, the activation of stress responses triggered by prion replication was not influenced by XBP-1 deficiency. Neither prion aggregation, neuronal loss, nor animal survival was affected. Hence, this most highly conserved arm of the UPR may not contribute to the occurrence or pathology of neurodegenerative conditions associated with prion protein misfolding despite predictions that such diseases are related to ER stress and irreversible neuronal damage.