Human prion diseases are fatal neurodegenerative disorders that include sporadic, infectious and genetic forms. Inherited Creutzfeldt-Jakob disease due to the E200K mutation of the prion protein-coding gene is the most common form of genetic prion disease. The phenotype resembles that of sporadic Creutzfeldt-Jakob disease at both the clinical and pathological levels, with a median disease duration of 4 months. To date, there is no available treatment for delaying the occurrence or slowing the progression of human prion diseases. Existing in vivo models do not allow high-throughput approaches that may facilitate the discovery of compounds targeting pathological assemblies of human prion protein or their effects on neuronal survival. Here, we generated a genetic model in the nematode Caenorhabditis elegans, which is devoid of any homologue of the prion protein, by expressing human prion protein with the E200K mutation in the mechanosensitive neuronal system. Expression of E200K prion protein induced a specific behavioural pattern and neurodegeneration of green fluorescent protein-expressing mechanosensitive neurons, in addition to the formation of intraneuronal inclusions associated with the accumulation of a protease-resistant form of the prion protein. We demonstrated that this experimental system is a powerful tool for investigating the efficacy of anti-prion compounds on both prion-induced neurodegeneration and prion protein misfolding, as well as in the context of human prion protein. Within a library of 320 compounds that have been approved for human use and cross the blood-brain barrier, we identified five molecules that were active against the aggregation of the E200K prion protein and the neurodegeneration it induced in transgenic animals. This model breaks a technological limitation in prion therapeutic research and provides a key tool to study the deleterious effects of misfolded prion protein in a well-described neuronal system.

We report a case of a 60-year-old man who presented with symptoms of memory loss, gait disorder, and sluggish movement. We considered both Parkinson's disease and multiple system atrophy as possible diagnoses and consequently hospitalized the patient owing to the worsening symptoms and the development of consciousness disorder. During the course of the disease, dementia, loss of consciousness, and movement disorders worsened rapidly within one year after admission, and the patient eventually developed mutism. The significant clinical characteristics of our case included no myoclonus and involuntary tremors in the extremities. There was no periodic synchronous discharge on electro-encephalography and cranial MRI with diffusion-weighted images showed no high-intensity findings in cortex. Prion protein genetic analysis identified four repeated insertional mutations in the octapeptide repeat (OPR) region, and the patient was diagnosed with inherited Creutzfeldt-Jakob disease. Cases of OPR insertional mutations are a few in Japan and occur in about 10% of population in Europe. Creutzfeldt-Jakob disease with OPR insertional mutation shows various clinical manifestations and atypical findings on electroencephalography and cranial MRI. Diagnosing for Creutzfeldt-Jakob disease with OPR insertional mutation is important in Prion protein genetic analysis.

Prion diseases are a group of rare neurodegenerative conditions characterised by a high rate of progression and highly heterogeneous phenotypes. Whilst the most common form of prion disease occurs sporadically (sporadic Creutzfeldt-Jakob disease, sCJD), other forms are caused by prion protein gene mutations, or exposure to prions in the diet or by medical procedures, such us surgeries. To date, there are no accurate quantitative imaging biomarkers that can be used to predict the future clinical diagnosis of a healthy subject, or to quantify the progression of symptoms over time. Besides, CJD is commonly mistaken for other forms of dementia. Due to the heterogeneity of phenotypes and the lack of a consistent geometrical pattern of disease progression, the approaches used to study other types of neurodegenerative diseases are not satisfactory to capture the progression of human form of prion disease. In this paper, using a tailored framework, we aim to classify and stratify patients with prion disease, according to the severity of their illness. The framework is initialised with the extraction of subject-specific imaging biomarkers. The extracted biomakers are then combined with genetic and demographic information within a Gaussian Process classifier, used to calculate the probability of a subject to be diagnosed with prion disease in the next year. We evaluate the effectiveness of the proposed method in a cohort of patients with inherited and sporadic forms of prion disease. The model has shown to be effective in the prediction of both inherited CJD (92% of accuracy) and sporadic CJD (95% of accuracy). However the model has shown to be less effective when used to stratify the different stages of the disease, in which the average accuracy is 85%, whilst the recall is 59%. Finally, our framework was extended as a differential diagnosis tool to identify both forms of CJD among another neurodegenerative disease. In summary we have developed a novel method for prion disease diagnosis and prediction of clinical onset using multiple sources of features, which may have use in other disorders with heterogeneous imaging features.

The cellular prion protein (PrPC) is a zinc-binding protein that contributes to the regulation of Zn2+ and other divalent species of the central nervous system. Zn2+ coordinates to the flexible, N-terminal repeat region of PrPC and drives a tertiary contact between this repeat region and a well-defined cleft of the C-terminal domain. The tertiary structure promoted by Zn2+ is thought to regulate inherent PrPC toxicity. Despite the emerging consensus regarding the interaction between Zn2+ and PrPC, there is little direct spectroscopic confirmation of the metal ion's coordination details. Here, we address this conceptual gap by using Cd2+ as a surrogate for Zn2+. NMR finds that Cd2+ binds exclusively to the His imidazole side chains of the repeat segment, with a dissociation constant of ∼1.2 mM, and promotes an N-terminal-C-terminal cis interaction very similar to that observed with Zn2+. Analysis of 113Cd NMR spectra of PrPC, along with relevant control proteins and peptides, suggests that coordination of Cd2+ in the full-length protein is consistent with a three- or four-His geometry. Examination of the mutation E199K in mouse PrPC (E200K in humans), responsible for inherited Creutzfeldt-Jakob disease, finds that the mutation lowers metal ion affinity and weakens the cis interaction. These findings not only provide deeper insight into PrPC metal ion coordination but they also suggest new perspectives on the role of familial mutations in prion disease.