[Qualitative analysis of the social and family impact of human transmissible spongiform encephalopathies]. / Analisis cualitativo del impacto social y familiar de las encefalopatias espongiformes transmisibles humanas.

INTRODUCTION: Human transmissible spongiform encephalopathies are pathologies related to the misfolding of the cellular prion protein. When these diseases manifest, they are characterized by a rapid and invariably fatal neurodegeneration. AIM: To gain insight on the social, personal and family reality of the people in close contact with these disorders. PATIENTS AND METHODS: Qualitative interviews were conducted online through semi-structured questionnaires open to carriers and first-degree relatives of those affected. The information was anonymous and the responses were requested to be broad. RESULTS: The sample consisted on 47 interviewees, seven confirmed carriers and 40 relatives that might be carriers or not. The majority of the informants were women aged between 30 and 50. The discourse analysis focused on their perception of the disease, time to diagnosis, and their uncertainties/needs allowed establishing four semantic fields: suffering/loss, temporality, medical/clinical and daily life. However, other important elements were also found. Only eight relatives considered necessary to increase research efforts. Relatives also presented a higher rate of uncertainty, while confirmed carriers did not show such uncertainty about their future. CONCLUSIONS: Socio-biomedical studies related to prion pathologies are rare. In this work, our knowledge on the social reality of the affected people and their close relatives is extended. These pathologies lead those in close contact with them to extremely complicated social situations with utmost psychosocial management difficulties.

TITLE: Analisis cualitativo del impacto social y familiar de las encefalopatias espongiformes transmisibles humanas.Introduccion. Las encefalopatias espongiformes transmisibles humanas son patologias relacionadas con el plegamiento incorrecto de la proteina prionica celular. Cuando estas se manifiestan, la neurodegeneracion producida es rapida y siempre letal. Objetivo. Describir y comprender la realidad social, personal y familiar de las personas afectadas. Pacientes y metodos. Se realizaron entrevistas cualitativas en linea a traves de cuestionarios semiestructurados abiertos a portadores y a las familias de afectados. La informacion fue anonima y se solicito que las respuestas fuesen amplias. Resultados. La muestra fue de 47 entrevistados, siete portadores confirmados y 40 familiares que podrian ser portadores o no. La mayoria de los informantes eran mujeres, con una edad comprendida, sobre todo, entre 30 y 50 años. El analisis del discurso, centrado en la percepcion de la propia enfermedad, el tiempo transcurrido hasta el diagnostico, y las incertidumbres y necesidades, ha permitido establecer cuatro campos semanticos: sufrimiento/perdida, temporalidad, medico/clinica y cotidianidad. No obstante, tambien se han encontrado otros elementos importantes. Solo ocho familiares consideran necesario incrementar la investigacion. Las familias presentan una alta tasa de incertidumbre; en cambio, los portadores no muestran tal incertidumbre ante su futuro. Conclusiones. Los estudios sociobiomedicos sobre patologias prionicas son poco habituales. En el trabajo se amplia el conocimiento sobre la realidad social de las personas y de las familias afectadas. Estas patologias ubican a los afectados en situaciones sociales muy complicadas y de dificil gestion psicosocial.

Prion Disease.

Prion diseases are a phenotypically diverse set of disorders characterized by protease-resistant abnormally shaped proteins known as prions. There are three main groups of prion diseases, termed sporadic (Creutzfeldt-Jakob disease [CJD], sporadic fatal insomnia, and variably protease-sensitive prionopathy), genetic (genetic CJD, fatal familial insomnia, and Gerstmann-Straussler-Scheinker syndrome), and acquired (kuru, variant CJD, and iatrogenic CJD). This article will review the pathophysiology, genetics, clinical presentations, and diagnostic challenges in patients with prion disease. Case discussions, images, and tables will be used to highlight important characteristics of prion disease and prion mimics.

A Novel Eight Octapeptide Repeat Insertion in PRNP Causing Prion Disease in a Danish Family.

Octapeptide repeat insertions (OPRI) found in the prion protein gene (PRNP) constitute a subgroup of pathogenic mutations linked to inherited prion diseases, a hallmark of which is a misfolded prion protein. The number of repeats in OPRI has been associated with different disease phenotypes. However, due to the rarity of the cases and heterogenous disease manifestations, the recognition and classification of these variants has been difficult. Here, we report the first Danish family, the fifth worldwide, carrying a novel 8-OPRI with a unique sequence of the additional 8 inserts: R1-R2-R2-R3-R2-R2-R2a-R2-R3g-R2-R2-R3-R4. The mutation was found on the allele coding for methionine at codon 129 in the PRNP gene. The clinical exome sequencing revealed that no other dementia-associated genes harbored pathogenic alterations. Mutation carriers had onset of symptoms in their early thirties, but disease duration varied from 5 to 11 years. Progressive dementia with psychiatric and motor symptoms were the most prominent clinical features. Clinical, pathological, and genetic characteristics of other 4 reported families with 8-OPRI were reviewed and compared with the findings in the Danish family.

Feasibility of Remote Assessment of Human Prion Diseases for Research and Surveillance.

BACKGROUND: Prion disease research and surveillance can be challenging due to the disease's difficulty to diagnose, rapid progression, and geographic dispersion. Improving accessibility through teleneurology could improve the ability to conduct these activities. OBJECTIVES: The aim of this study was to determine the feasibility of conducting teleneurology assessments for research and surveillance of prion diseases. METHOD: Participants were offered in-person visit, medical record review, or teleneurology assessment. Standardized histories and assessments evaluating cognition, functional ability, and neuropsychiatric symptoms were collected. Data regarding participants' satisfaction with teleneurology were collected. RESULTS: From April 2017 to July 2018, the study received 114 referrals. 45 and 5 participants consented for the teleneurology and medical record review arms of the study, respectively. 29 subjects participated in at least one teleneurology visit. Participants expressed satisfaction with teleneurology and found it easy to participate. Some aspects of the examination were hindered or interrupted due to technological reasons. CONCLUSIONS: We demonstrate the feasibility and preference of teleneurology as a modality in which subjects with prion disease can partake in clinical research. Technological aspects sometimes interfered with research assessments.

The most problematic symptoms of prion disease - an analysis of carer experiences.

OBJECTIVES: Prion diseases are rare dementias that most commonly occur sporadically, but can be inherited or acquired, and for which there is no cure. We sought to understand which prion disease symptoms are most problematic for carers, to inform the development of outcome measures. DESIGN: Self-completed questionnaire with follow-up of a subset of participants by structured interview. SETTING: A nested study in the UK National Prion Monitoring Cohort, a longitudinal observational study. PARTICIPANTS AND MEASUREMENTS: 71 carers, of people with different prion diseases with a wide range of disease severity, identified 236 of their four most problematic symptoms by questionnaire which were grouped into ten domains. Structured interviews were then done to qualitatively explore these experiences. Eleven family carers of people with prion disease were selected, including those representative of a range of demographics and disease subtypes and those who cared for people with prion disease, living or recently deceased. Interviews were transcribed and formally studied. RESULTS: The six most problematic symptom domains were: mobility and coordination; mood and behavior; personal care and continence; eating and swallowing; communication; and cognition and memory. The prevalence of these symptoms varied significantly by disease stage and type. A formal analysis of structured interviews to explore these domains is reported. CONCLUSIONS: We make suggestions about how healthcare professionals can focus their support for people with prion disease. Clinical trials that aim to generate evidence regarding therapies that might confer meaningful benefits to carers should consider including outcome measures that monitor the symptomatic domains we have identified as problematic.

Age and Environment Influences on Mouse Prion Disease Progression: Behavioral Changes and Morphometry and Stereology of Hippocampal Astrocytes.

Because enriched environment (EE) and exercise increase and aging decreases immune response, we hypothesized that environmental enrichment and aging will, respectively, delay and increase prion disease progression. Mice dorsal striatum received bilateral stereotaxic intracerebral injections of normal or ME7 prion infected mouse brain homogenates. After behavior analysis, animals were euthanized and their brains processed for astrocyte GFAP immunolabeling. Our analysis related to the environmental influence are limited to young adult mice, whereas age influence refers to aged mice raised on standard cages. Burrowing activity began to reduce in ME7-SE two weeks before ME7-EE, while no changes were apparent in ME7 aged mice (ME7-A). Object placement recognition was impaired in ME7-SE, NBH-A, and ME7-A but normal in all other groups. Object identity recognition was impaired in ME7-A. Cluster analysis revealed two morphological families of astrocytes in NBH-SE animals, three in NBH-A and ME7-A, and four in NBH-EE, ME7-SE, and ME7-EE. As compared with control groups, astrocytes from DG and CA3 prion-diseased animals show significant numerical and morphological differences and environmental enrichment did not reverse these changes but induced different morphological changes in GFAP+ hippocampal astroglia. We suggest that environmental enrichment and aging delayed hippocampal-dependent behavioral and neuropathological signs of disease progression.

Systemic TNF-α produces acute cognitive dysfunction and exaggerated sickness behavior when superimposed upon progressive neurodegeneration.

Inflammation influences chronic neurodegeneration but its precise roles are not yet clear. Systemic inflammation caused by infection, trauma or co-morbidity can alter the brain's inflammatory status, produce acute cognitive impairments, such as delirium, and drive new pathology and accelerated decline. Consistent with this, elevated systemic TNF-α is associated with more rapid cognitive decline over 6months in Alzheimer's disease patients. In the current study we challenged normal animals and those with existing progressive neurodegeneration (ME7 prion disease) with TNF-α (i.p.) to test the hypothesis that this cytokine has differential effects on cognitive function, sickness behavior and features of underlying pathology contingent on the animals' baseline condition. TNF-α (50µg/kg) had no impact on performance of normal animals (normal brain homogenate; NBH) on working memory (T-maze) but produced acute impairments in ME7 animals similarly challenged. Plasma TNF-α and CCL2 levels were equivalent in NBH and ME7 TNF-challenged animals but hippocampal and hypothalamic transcription of IL-1ß, TNF-α and CCL2 and translation of IL-1ß were higher in ME7+TNF-α than NBH+TNF-α animals. TNF-α produced an exaggerated sickness behavior response (hypothermia, weight loss, inactivity) in ME7 animals compared to that in NBH animals. However a single challenge with this dose was not sufficient to produce de novo neuronal death, synaptic loss or tau hyperphosphorylation that was distinguishable from that arising from ME7 alone. The data indicate that acutely elevated TNF-α has robust acute effects on brain function, selectively in the degenerating brain, but more sustained levels may be required to significantly impact on underlying neurodegeneration.

Virus Infections on Prion Diseased Mice Exacerbate Inflammatory Microglial Response.

We investigated possible interaction between an arbovirus infection and the ME7 induced mice prion disease. C57BL/6, females, 6-week-old, were submitted to a bilateral intrahippocampal injection of ME7 prion strain (ME7) or normal brain homogenate (NBH). After injections, animals were organized into two groups: NBH (n = 26) and ME7 (n = 29). At 15th week after injections (wpi), animals were challenged intranasally with a suspension of Piry arbovirus 0.001% or with NBH. Behavioral changes in ME7 animals appeared in burrowing activity at 14 wpi. Hyperactivity on open field test, errors on rod bridge, and time reduction in inverted screen were detected at 15th, 19th, and 20th wpi respectively. Burrowing was more sensitive to earlier hippocampus dysfunction. However, Piry-infection did not significantly affect the already ongoing burrowing decline in the ME7-treated mice. After behavioral tests, brains were processed for IBA1, protease-resistant form of PrP, and Piry virus antigens. Although virus infection in isolation did not change the number of microglia in CA1, virus infection in prion diseased mice (at 17th wpi) induced changes in number and morphology of microglia in a laminar-dependent way. We suggest that virus infection exacerbates microglial inflammatory response to a greater degree in prion-infected mice, and this is not necessarily correlated with hippocampal-dependent behavioral deficits.

[Psychiatric manifestations by prions. A narrative review]. / Manifestaciones psiquiátricas por priones. Una revisión narrativa.

Prion diseases are a group of rare and rapidly progressive neurodegenerative conditions that may cause neuropsychiatric symptoms. This group of diseases has been described since the 18(th) century, but they were recognized decades later, when it became clear that the humans were affected by infected animals. There was controversy when the problem was attributed to a single protein with infective capacity. The common pathological process is characterized by the conversion of the normal cellular prion protein into an abnormal form. In humans, the illness has been classified as idiopathic, inherited and acquired through exposure to exogenous material containing abnormal prions. The most prominent neurological manifestation of prion diseases is the emergence of a rapidly progressive dementia, mioclonus associated with cerebellar ataxia and also extra pyramidal symptoms. Psychiatric symptoms occur in early stages of the illness and can contribute to timely diagnosis of this syndrome. Psychiatric symptoms have traditionally been grouped in three categories: affective symptoms, impaired motor function and psychotic symptoms. Such events usually occur during the prodromal period prior to the neurological manifestations and consists in the presence of social isolation, onset of delusions, irritability/aggression, visual hallucinations, anxiety and depression, and less frequent first-rank symptoms among others. Definite diagnosis requires post mortem examination. The possibility that a large number of cases may occur in the next years or that many cases have not been considered with this diagnosis is a fact. In our opinion, psychiatrists should be aware of symptoms of this disease. The main objective of this research consisted of assessing the correlation between this disturbance and neuro-psychiatric symptoms and particularly if this psychiatric manifestations integrate a clinical picture suggestive for the diagnosis of these diseases, but firstly reviewed taxonomic, pathogenic and pathological aspects. The authors of this project also added an element in relation to some diagnostic considerations based on scientific evidence. For the search controlled descriptors applied to the research for indexing scientific articles in databases were used. The electronic data bases used were PubMed, EMBASE and also PsycInfo. The descriptors were prion diseases, psychotic disorders, depression, mood disorders, pathology, classification, prion protein, history, neurological manifestations, and psychiatric manifestations. The selection criteria for the material were qualitative. To conclude, and based on the extensive literature review, the authors propose that the period where the evidence is more robust for mental impaired is named "psychiatric symptoms phase, which can be extended for a few months, being the psychiatric affective symptoms the most characteristic of this phase. In conclusion, we considered that the identification of these symptoms in a patient with risk factors for developing the disease will contribute to the early identification, and would regulate the guidelines in suspected diagnosis of this group of disorders. The intention is provide a better quality of life to the sick people.

Genome-wide association study of behavioural and psychiatric features in human prion disease.

Prion diseases are rare neurodegenerative conditions causing highly variable clinical syndromes, which often include prominent neuropsychiatric symptoms. We have recently carried out a clinical study of behavioural and psychiatric symptoms in a large prospective cohort of patients with prion disease in the United Kingdom, allowing us to operationalise specific behavioural/psychiatric phenotypes as traits in human prion disease. Here, we report exploratory genome-wide association analysis on 170 of these patients and 5200 UK controls, looking for single-nucleotide polymorphisms (SNPs) associated with three behavioural/psychiatric phenotypes in the context of prion disease. We also specifically examined a selection of candidate SNPs that have shown genome-wide association with psychiatric conditions in previously published studies, and the codon 129 polymorphism of the prion protein gene, which is known to modify various aspects of the phenotype of prion disease. No SNPs reached genome-wide significance, and there was no evidence of altered burden of known psychiatric risk alleles in relevant prion cases. SNPs showing suggestive evidence of association (P<10(-5)) included several lying near genes previously implicated in association studies of other psychiatric and neurodegenerative diseases. These include ANK3, SORL1 and a region of chromosome 6p containing several genes implicated in schizophrenia and bipolar disorder. We would encourage others to acquire phenotype data in independent cohorts of patients with prion disease as well as other neurodegenerative and neuropsychiatric conditions, to allow meta-analysis that may shed clearer light on the biological basis of these complex disease manifestations, and the diseases themselves.

Reduced expression of the presynaptic co-chaperone cysteine string protein alpha (CSPα) does not exacerbate experimentally-induced ME7 prion disease.

Infection of mice with the ME7 prion agent results in well-characterised neuropathological changes, which includes vacuolation, neurodegeneration and synaptic degeneration. Presynaptic dysfunction and degeneration is apparent through the progressive reduction in synaptic vesicle proteins and eventual loss of synapses. Cysteine string protein alpha (CSPα), which regulates refolding pathways at the synapse, exhibits an early decline during chronic neurodegeneration implicating it as a mediator of disease mechanisms. CSPα null mice develop a progressive neuronal dysfunction through disruption of the integrity of presynaptic function. In this study, we investigated whether reduced expression of CSPα would exacerbate ME7 prion disease. Wild type (+/+) and heterozygous (+/-) mice, which express about a ∼50% reduction in CSPα, were used as a distinct genetic background on which to impose prion disease. +/+ and +/ - mice were inoculated with brain homogenate from either a normal mouse brain (NBH) or from the brain of a mouse which displayed clinical signs of prion disease (ME7). Behavioural tests, western blotting and immunohistochemistry, which resolve key elements of synaptic dysfunction, were used to assess the effect of reduced CSPα on disease. Behavioural tests revealed no change in the progression of disease in ME7-CSPα +/- animals compared to ME7-CSPα +/+ animals. In addition, the accumulation of misfolded PrP(Sc), the diseased associated gliosis or synaptic loss were not different. Thus, the misfolding events that generate synaptic dysfunction and lead to synaptic loss are unlikely to be mediated by a disease associated decrease in the refolding pathways associated with CSPα.

Behavioral and psychiatric symptoms in prion disease.

The prion diseases are rare neurodegenerative conditions that cause complex and highly variable neuropsychiatric syndromes, often with remarkably rapid progression. Prominent behavioral and psychiatric symptoms have been recognized since these diseases were first described. While research on such symptoms in common dementias has led to major changes in the way these symptoms are managed, evidence to guide the care of patients with prion disease is scarce. The authors review the published research and draw on more than 10 years' experience at the U.K. National Prion Clinic, including two large prospective clinical research studies in which more than 300 patients with prion disease have been followed up from diagnosis to death, with detailed observational data gathered on symptomatology and symptomatic treatments. The authors group behavioral and psychiatric symptoms into psychotic features, agitated features, and mood disorder and describe their natural history, showing that they spontaneously improve or resolve in many patients and are short-lived in many others because of rapid progression of global neurological disability. Diagnostic category, disease severity, age, gender, and genetic variation are or may be predictive factors. The authors review the observational data on pharmacological treatment of these symptoms in the U.K. clinical studies and make cautious recommendations for clinical practice. While nonpharmacological measures should be the first-line interventions for these symptoms, the authors conclude that there is a role for judicious use of pharmacological agents in some patients: antipsychotics for severe psychosis or agitation; benzodiazepines, particularly in the late stages of disease; and antidepressants for mood disorder.

Early Hippocampal Synaptic Loss Precedes Neuronal Loss and Associates with Early Behavioural Deficits in Three Distinct Strains of Prion Disease.

Prion diseases are fatal neurodegenerative diseases of the CNS that are associated with the accumulation of misfolded cellular prion protein. There are several different strains of prion disease defined by different patterns of tissue vacuolation in the brain and disease time course, but features of neurodegeneration in these strains have not been extensively studied. Our previous studies using the prion strains ME7, 79A and 22L showed that infected mice developed behavioural deficits in the same sequence and temporal pattern despite divergent end-stage neuropathology. Here the objective was to address the hypothesis that synaptic loss would occur early in the disease in all three strains, would precede neuronal death and would be associated with the early behavioural deficits. C57BL/6 mice inoculated with ME7, 79A, or 22L-infected brain homogenates were behaviourally assessed on species typical behaviours previously shown to change during progression and euthanised when all three strains showed statistically significant impairment on these tasks. A decrease in labelling with the presynaptic marker synaptophysin was observed in the stratum radiatum of the hippocampus in all three strains, when compared to control animals. Negligible cell death was seen by TUNEL at this time point. Astrocyte and microglial activation and protease resistant prion protein (PrP(Sc)) deposition were assessed in multiple brain regions and showed some strain specificity but also strongly overlapping patterns. This study shows that despite distinct pathology, multiple strains lead to early synaptic degeneration in the hippocampus, associated with similar behavioural deficits and supports the idea that the initiation of synaptic loss is a primary target of the misfolded prion agent.

Early behavioral changes and quantitative analysis of neuropathological features in murine prion disease: stereological analysis in the albino Swiss mice model.

Behavioral and neuropathological changes have been widely investigated in murine prion disease but stereological based unbiased estimates of key neuropathological features have not been carried out. After injections of ME7 infected (ME7) or normal brain homogenates (NBH) into dorsal CA1 of albino Swiss mice and C57BL6, we assessed behavioral changes on hippocampal-dependent tasks. We also estimated by optical fractionator at 15 and 18 weeks post-injections (w.p.i.) the total number of neurons, reactive astrocytes, activated microglia and perineuronal nets (PN) in the polymorphic layer of dentate gyrus (PolDG), CA1 and septum in albino Swiss mice. On average, early behavioral changes in albino Swiss mice start four weeks later than in C57BL6. Cluster and discriminant analysis of behavioral data in albino Swiss mice revealed that four of nine subjects start to change their behavior at 12 w.p.i. and reach terminal stage at 22 w.p.i and the remaining subjects start at 22 w.p.i. and reach terminal stage at 26 w.p.i. Biotinylated dextran-amine BDA-tracer experiments in mossy fiber pathway confirmed axonal degeneration, and stereological data showed that early astrocytosis, microgliosis and reduction in the perineuronal nets are independent of a change in the number of neuronal cell bodies. Statistical analysis revealed that the septal region had greater levels of neuroinflammation and extracellular matrix damage than CA1. This stereological and multivariate analysis at early stages of disease in an outbred model of prion disease provided new insights connecting behavioral changes and neuroinflammation and seems to be important to understand the mechanisms of prion disease progression.

Familial prion disease with Alzheimer disease-like tau pathology and clinical phenotype.

OBJECTIVE: To describe the Alzheimer disease (AD)-like clinical and pathological features, including marked neurofibrillary tangle (NFT) pathology, of a familial prion disease due to a rare nonsense mutation of the prion gene (PRNP). METHODS: Longitudinal clinical assessments were available for the proband and her mother. After death, both underwent neuropathological evaluation. PRNP was sequenced after failure to find immunopositive Aß deposits in the proband and the documentation of prion protein (PrP) immunopositive pathology. RESULTS: The proband presented at age 42 years with a 3-year history of progressive short-term memory impairment and depression. Neuropsychological testing found impaired memory performance, with relatively preserved attention and construction. She was diagnosed with AD and died at age 47 years. Neuropathologic evaluation revealed extensive limbic and neocortical NFT formation and neuritic plaques consistent with a Braak stage of VI. The NFTs were immunopositive, with multiple tau antibodies, and electron microscopy revealed paired helical filaments. However, the neuritic plaques were immunonegative for Aß, whereas immunostaining for PrP was positive. The mother of the proband had a similar presentation, including depression, and had been diagnosed clinically and pathologically as AD. Reevaluation of her brain tissue confirmed similar tau and PrP immunostaining findings. Genetic analysis revealed that both the proband and her mother had a rare PRNP mutation (Q160X) that resulted in the production of truncated PrP. INTERPRETATION: We suggest that PRNP mutations that result in a truncation of PrP lead to a prolonged clinical course consistent with a clinical diagnosis of AD and severe AD-like NFTs.

Using qualitative methods to investigate risk perception of Canadian medical laboratory workers in relation to current prion disease infection control policies.

The aim of this study was to determine the rationale, methodology, and progress of risk perceptions of laboratory workers in relation to existing prion disease infection control policies in Canadian medical laboratories. This study developed a Web survey that investigated the knowledge, behavior, and attitudes of laboratory staff in order to (1) identify strengths, weaknesses, and gaps of current prion infection prevention and control guidelines and (2) inform the development of national medical lab specific guidelines. The use of qualitative methods to develop a relevant survey is described and future research activities are outlined. Preliminary, qualitative data indicate that, among laboratory staff, there is a high degree of perceived susceptibility toward prion transmission in medical laboratories. Significant barriers to following existing prion infection control guidelines are reported with few benefits of following these guidelines. As a result, laboratories take precautions above those that are required when processing suspect prion-infected specimens, which may result in testing delays. A focused survey for laboratory staff that addresses these issues will provide insight on the necessary steps that will ensure safe and efficient diagnostic testing for suspect prion specimens.

The prion diseases.

The prion diseases are a family of rare neurodegenerative disorders that result from the accumulation of a misfolded isoform of the prion protein (PrP), a normal constituent of the neuronal membrane. Five subtypes constitute the known human prion diseases; kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal insomnia (FI), and variant CJD (vCJD). These subtypes are distinguished, in part, by their clinical phenotype, but primarily by their associated brain histopathology. Evidence suggests these phenotypes are defined by differences in the pathogenic conformation of misfolded PrP. Although the vast majority of cases are sporadic, 10% to 15% result from an autosomal dominant mutation of the PrP gene (PRNP). General phenotype-genotype correlations can be made for the major subtypes of CJD, GSS, and FI. This paper will review some of the general background related to prion biology and detail the clinical and pathologic features of the major prion diseases, with a particular focus on the genetic aspects that result in prion disease or modification of its risk or phenotype.

Single treatment with RNAi against prion protein rescues early neuronal dysfunction and prolongs survival in mice with prion disease.

Prion diseases are fatal neurodegenerative conditions for which there is no effective treatment. Prion propagation involves the conversion of cellular prion protein, PrP(C), to its conformational isomer, PrP(Sc), which accumulates in disease. Here, we show effective therapeutic knockdown of PrP(C) expression using RNAi in mice with established prion disease. A single administration of lentivirus expressing a shRNA targeting PrP into each hippocampus of mice with established prion disease significantly prolonged survival time. Treated animals lived 19% and 24% longer than mice given an "empty" lentivirus, or not treated, respectively. Lentivirally mediated RNAi of PrP also prevented the onset of behavioral deficits associated with early prion disease, reduced spongiform degeneration, and protected against neuronal loss. In contrast, mice receiving empty virus or no treatment developed early cognitive impairment and showed severe spongiosis and neuronal loss. The focal use of RNAi therapeutically in prion disease further supports strategies depleting PrP(C), which we previously established to be a valid target for prion-based treatments. This approach can now be used to define the temporal, quantitative, and regional requirements for PrP knockdown for effective treatment of prion disease and to explore mechanisms involved in predegenerative neuronal dysfunction and its rescue.