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Sporadic Creutzfeldt-Jakob disease is a fatal neurodegenerative disease caused by misfolded prion proteins (PrPSc). Effective therapeutics are currently not available and accurate diagnosis can be challenging. Clinical diagnostic criteria use a combination of characteristic neuropsychiatric symptoms, CSF proteins 14-3-3, MRI, and EEG. Supportive biomarkers, such as high CSF total tau, could aid the diagnostic process. However, discordant studies have led to controversies about the clinical value of some established surrogate biomarkers. Development and clinical application of disease-specific protein aggregation and amplification assays, such as real-time quaking induced conversion (RT-QuIC), have constituted major breakthroughs for the confident pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Updated criteria for the diagnosis of sporadic Creutzfeldt-Jakob disease, including application of RT-QuIC, should improve early clinical confirmation, surveillance, assessment of PrPSc seeding activity in different tissues, and trial monitoring. Moreover, emerging blood-based, prognostic, and potentially pre-symptomatic biomarker candidates are under investigation.

The misfolding of the cellular prion protein (PrP C ) causes fatal neurodegenerative diseases. Yet PrP C is highly conserved in mammals, suggesting that it exerts beneficial functions preventing its evolutionary elimination. Ablation of PrP C in mice results in well-defined structural and functional alterations in the peripheral nervous system. Many additional phenotypes were ascribed to the lack of PrP C , but some of these were found to arise from genetic artifacts of the underlying mouse models. Here, we revisit the proposed physiological roles of PrP C in the central and peripheral nervous systems and highlight the need for their critical reassessment using new, rigorously controlled animal models.

The current classification of sporadic Creutzfeldt–Jakob disease (sCJD) includes six major clinicopathological subtypes defined by the physicochemical properties of the protease-resistant core of the pathologic prion protein (PrPSc), defining two major PrPSc types (i.e., 1 and 2), and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein gene (PRNP). How these sCJD subtypes relate to the well-documented phenotypic heterogeneity of genetic CJD (gCJD) is not fully understood. We analyzed molecular and phenotypic features in 208 individuals affected by gCJD, carrying 17 different mutations, and compared them with those of a large series of sCJD cases. We identified six major groups of gCJD based on the combination PrPSc type and codon 129 genotype on PRNP mutated allele, each showing distinctive histopathological characteristics, irrespectively of the PRNP associated mutation. Five gCJD groups, named M1, M2C, M2T, V1, and V2, largely reproduced those previously described in sCJD subtypes. The sixth group shared phenotypic traits with the V2 group and was only detected in patients carrying the E200K-129M haplotype in association with a PrPSc type of intermediate size (“i”) between type 1 and type 2. Additional mutation-specific effects involved the pattern of PrP deposition (e.g., a “thickened” synaptic pattern in E200K carriers, cerebellar “stripe-like linear granular deposits” in those with insertion mutations, and intraneuronal globular dots in E200K-V2 or -M”i”). A few isolated cases linked to rare PRNP haplotypes (e.g., T183A-129M), showed atypical phenotypic features, which prevented their classification into the six major groups. The phenotypic variability of gCJD is mostly consistent with that previously found in sCJD. As in sCJD, the codon 129 genotype and physicochemical properties of PrPSc significantly correlated with the phenotypic variability of gCJD. The most common mutations linked to CJD appear to have a variable and overall less significant effect on the disease phenotype, but they significantly influence disease susceptibility often in a strain-specific manner. The criteria currently used for sCJD subtypes can be expanded and adapted to gCJD to provide an updated classification of the disease with a molecular basis.

Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) that affects members of the cervidae family. The infectious agent is a misfolded isoform (PrPSC) of the host prion protein (PrPC). The replication of PrPSC initiates a cascade of developmental changes that spread from cell to cell, individual to individual, and that for some TSEs, has crossed the species barrier. CWD can be transmitted horizontally and vertically, and it is the only TSE that affects free-ranging wildlife. While other TSEs are under control and even declining, infection rates of CWD continue to grow and the disease distribution continues to expand in North America and around the world. Since the first reported case in 1967, CWD has spread infecting captive and free-ranging cervids in 26 states in the US, 3 Canadian provinces, 3 European countries and has been found in captive cervids in South Korea. CWD causes considerable ecologic, economic and sociologic impact, as this is a 100% fatal highly contagious infectious disease, with no treatment or cure available. Because some TSEs have crossed the species barrier, the zoonotic potential of CWD is a concern for human health and continues to be investigated. Here we review the characteristics of the CWD prion protein, mechanisms of transmission and the role of genetics. We discuss the characteristics that contribute to prevalence and distribution. We also discuss the impact of CWD and review the management strategies that have been used to prevent and control the spread of CWD.

Genetic Creutzfeldt–Jakob disease (gCJD) with V180I prion protein gene (PRNP) mutation shows weaker prion protein (PrP) deposition histologically compared with sporadic CJD, and it is more difficult to detect protease‐resistant prion protein in immunoblotting. However, we previously reported the autopsy case of a patient with V180I gCJD who was treated with pentosan polysulfate sodium (PPS); this case had increased protease‐resistant PrP deposition. It has been suggested that PPS might reduce protease‐resistant PrP; however, the detailed pharmacological and histopathological effects of PPS in humans remain unknown. We examined autopsied human brain tissue from four cases with V180I gCJD that were added to our archives between 2011 and 2021: two cases treated with PPS and two cases without PPS. We conducted a neuropathological assessment, including immunohistochemistry for PrP. We also performed immunoblotting for PrP on homogenate samples from each brain to detect protease‐resistant PrP using both a conventional procedure and size‐exclusion gel chromatography for the purification of oligomeric PrP. Both PPS‐treated cases showed long survival time over 5 years from onset and increased PrP deposition with a characteristic pattern of coarse granular depositions and congophilic PrP microspheres, whereas the cases without PPS showed around 1‐year survival from onset and relatively mild neuronal loss and synaptic PrP deposition. Although cortical gliosis seemed similar among all cases, aquaporin 4‐expression as a hallmark of astrocytic function was increased predominantly in PPS cases. Immunoblotting of non‐PPS cases revealed protease‐resistant PrP in the oligomeric fraction only, whereas the PPS‐treated cases showed clear signals using conventional procedures and in the oligomeric fraction. These unique biochemical and histopathological changes may reflect the progression of V180I gCJD and its modification by PPS, suggesting the possible existence of toxic PrP‐oligomer in the pathophysiology of V180I gCJD and beneficial effects of PPS toward the aggregation and detoxication of toxic PrP‐oligomer. PrP‐positive microspheres in pentosan polysulfate sodium (PPS)‐administrated V180I‐gCJD cases. The images in (A‐D, G, H) show the cerebral cortex and (E,F) show the thalamus. Arrows indicate microspheres, arrowheads indicate foamy spheroid bodies. (A,C,E): hematoxylin–eosin staining, (B,D,F): immunohistochemistry for prion protein (PrP; clone 3F4), (G,H): Congo red staining (G: brightfield image, H: polarized image). The images in (I–L) show immunohistochemistry (I) and immunoelectron microscopy (J–L) for PrP (clone 3F4) on the same section of PPS case. PrP‐positive microspheres are indicated by black arrows (I,J). The images in (K–P) show higher magnification of PrP‐positive microspheres.

 In this study, a known mutation, Val180Ile (c.G538A), was reported in a 58 years old female patient, clinically diagnosed with Alzheimer's disease (AD). The patient presented slowly progressive cognitive decline in memory and visuospatial domain. Neuroimaging showed hippocampal atrophy in MRI and mild amyloid positivity in PET scan. Even though her cerebrospinal fluid (CSF) was positive for 14-3-3 protein, no sign of Creutzfeldt-Jakob diseases symptoms was observed. In addition, reduced Aβ42 and elevated total-Tau and phospho-Tau in CSF also proved the AD diagnosis. The mutation may disturb the hydrophobic core of prion protein, and result in abnormal intramolecular interactions. Due to 23andMe, Val180Ile could not be categorized either as a mutation with complete penetrance, or as neutral variant, and could have a possible role in neurodegeneration. Pathological overlap was observed between prion diseases and other neurodegenerative diseases, including AD or frontotemporal dementia. Whole exome sequencing and pathway analysis of patient revealed rare or possible risk variants in AD associated genes, such as SORL1 or ABCA7. Along with , AD risk genes may play a role in negative regulation of amyloid formation. Dysfunctions in these genes could possibly be associated in reduced neuroprotection and amyloid clearance.

Transmissible Spongiform Encephalopathies (TSEs) or prion diseases are a fatal group of infectious, inherited and spontaneous neurodegenerative diseases affecting human and animals. They are caused by the conversion of cellular prion protein (PrPC) into a misfolded pathological isoform (PrPSc or prion- proteinaceous infectious particle) that self-propagates by conformational conversion of PrPC. Yet by an unknown mechanism, PrPC can fold into different PrPSc conformers that may result in different prion strains that display specific disease phenotype (incubation time, clinical signs and lesion profile). Although the pathways for neurodegeneration as well as the involvement of brain inflammation in these diseases are not well understood, the spongiform changes, neuronal loss, gliosis and accumulation of PrPSc are the characteristic neuropathological lesions. Scrapie affecting small ruminants was the first identified TSE and has been considered the archetype of prion diseases, though atypical and new animal prion diseases continue to emerge highlighting the importance to investigate the lesion profile in naturally affected animals. In this report, we review the neuropathology and the neuroinflammation of animal prion diseases in natural hosts from scrapie, going through the zoonotic bovine spongiform encephalopathy (BSE), the chronic wasting disease (CWD) to the newly identified camel prion disease (CPD).

Prion diseases, including chronic wasting disease (CWD) in cervids, are fatal neurodegenerative disorders caused by the misfolding of cellular prion proteins. CWD is known to spread among captive and free-ranging deer in North America. In 2016, an outbreak of contagious CWD was detected among wild reindeer in Norway, marking the first occurrence of the disease in Europe. Additionally, new sporadic forms of CWD have been discovered in red deer in Norway and moose in Fennoscandia. We used serial protein misfolding cyclic amplification to study the ability of Norwegian prion isolates from reindeer, red deer, and moose (two isolates), as well as experimental classical scrapie from sheep, to convert a panel of 16 brain homogenates (substrates) from six different species with various prion protein genotypes. The reindeer CWD isolate successfully converted substrates from all species except goats. The red deer isolate failed to convert sheep and goat substrates but exhibited amplification in all cervid substrates. The two moose isolates demonstrated lower conversion efficacies. The wild type isolate propagated in all moose substrates and in the wild type red deer substrate, while the other isolate only converted two of the moose substrates. The experimental classical scrapie isolate was successfully propagated in substrates from all species tested. Thus, reindeer CWD and classical sheep scrapie isolates were similarly propagated in substrates from different species, suggesting the potential for spillover of these contagious diseases. Furthermore, the roe deer substrate supported conversion of three isolates suggesting that this species may be vulnerable to prion disease.

Chronic wasting disease (CWD) is well known among cervids in North America. Nevertheless, management faced different types and degrees of uncertainty when CWD was first detected in reindeer Rangifer tarandus in Nordfjella, Norway in 2016. We present a timeline of the efforts to control CWD, and identify how the process, measurement, environmental, and implementation uncertainties developed from the onset (2016) to the current situation (2023) after seven years of CWD management. In the ‘acute' phase (2016–2019), political ambitions were high and depopulation of the Nordfjella reindeer area involving marksmen aimed at eradicating CWD. Subsequently, increased surveillance and increased male harvest was used to enable early detection or to achieve ‘freedom‐from‐CWD' status of the adjacent populations. The second phase (2020‐now) came when cases were detected in the large reindeer population in Hardangervidda. Management authorities postponed culling using marksmen, signifying an important change, with more emphasis on socio‐political acceptance and consideration of the negative long‐term consequences of conflicts with local stakeholders. The subsequent dialogue processes between scientists and local management ended in joint advice. However, the Ministry set aside all advice in 2022, halting further actions, after pressure and negative media attention. During this period, there was no clear research plan to increase knowledge of CWD to reduce process uncertainty; however, large surveillance investments were made to reduce measurement uncertainty. Despite this, detecting and estimating CWD among reindeer at low prevalence remains a key challenge. Governance challenges have emerged as significant implementation uncertainties, partly due to the uncertain occurrence of CWD.

The cellular prion protein, encoded by the gene Prnp, has been reported to be a receptor of β-amyloid. Their interaction is mandatory for neurotoxic effects of β-amyloid oligomers. In this study, we aimed to explore whether the cellular prion protein participates in the spreading of α-synuclein. Results demonstrate that Prnp expression is not mandatory for α-synuclein spreading. However, although the pathological spreading of α-synuclein can take place in the absence of Prnp, α-synuclein expanded faster in PrPC-overexpressing mice. In addition, α-synuclein binds strongly on PrPC-expressing cells, suggesting a role in modulating the effect of α-synuclein fibrils.