• Chronic wasting disease
• Glycosylation
• Prion
• Prion strains
• Transmissible spongiform encephalopathies

• Animals
• Arvicolinae
• Glycosylation
• Mice, Transgenic
• Wasting Disease, Chronic/metabolism
• Wasting Disease, Chronic/pathology
• Wasting Disease, Chronic/genetics
• Mice
• PrPC Proteins/metabolism
• PrPC Proteins/genetics
• Glycosylphosphatidylinositols/metabolism
• Brain/pathology
• Brain/metabolism

• Bank voles
• Knock-in mice
• Mass spectrometry
• Prion
• Protein-protein interactions

• Animals
• Brain/metabolism
• Mice
• Arvicolinae
• Prions/metabolism
• Prions/genetics
• Gene Knock-In Techniques
• Mice, Transgenic
• Mice, Inbred C57BL

• SNP
• SPRN
• Sho
• genetic polymorphism
• pekin ducks
• prion

• 2021R1A2C1013213, 2022R1C1C2004792 National Research Foundation of Korea (NRF)
• 2017R1A6A1A03015876, 2021R1A6A3A01086488 Ministry of Education
• 2021R1A6C101C369 Korea Basic Science Institute

• Humans
• Prion Proteins
• Prions
• Prion Diseases/metabolism

The metazoan Hsp70 disaggregase protects neurons from proteotoxicity that arises from the accumulation of misfolded protein aggregates. Hsp70 and its co-chaperones disassemble and extract polypeptides from protein aggregates for refolding or degradation. The effectiveness of the chaperone system decreases with age and leads to accumulation rather than removal of neurotoxic protein aggregates. Therapeutic enhancement of the Hsp70 protein disassembly machinery is proposed to counter late-onset protein misfolding neurodegenerative disease that may arise. In the context of prion disease, it is not known whether stimulation of protein aggregate disassembly paradoxically leads to enhanced formation of seeding competent species of disease-specific proteins and acceleration of neurodegenerative disease. Here we have tested the hypothesis that modulation of Hsp70 disaggregase activity perturbs mammalian prion-induced neurotoxicity and prion seeding activity. To do so we used prion protein (PrP) transgenic Drosophila that authentically replicate mammalian prions. RNASeq identified that Hsp70, DnaJ-1 and Hsp110 gene expression was downregulated in prion-exposed PrP Drosophila. We demonstrated that RNAi knockdown of Hsp110 or DnaJ-1 gene expression in variant Creutzfeldt–Jakob disease prion-exposed human PrP Drosophila enhanced neurotoxicity, whereas overexpression mitigated toxicity. Strikingly, prion seeding activity in variant Creutzfeldt–Jakob disease prion-exposed human PrP Drosophila was ablated or reduced by Hsp110 or DnaJ-1 overexpression, respectively. Similar effects were seen in scrapie prion-exposed ovine PrP Drosophila with modified Hsp110 or DnaJ-1 gene expression. These unique observations show that the metazoan Hsp70 disaggregase facilitates the clearance of mammalian prions and that its enhanced activity is a potential therapeutic strategy for human prion disease.

• Drosophila
• heat shock protein
• neurodegeneration
• nucleotide exchange factor
• prion

• Biomarkers
• Epigenetics
• Genomics
• Prion diseases

• nerves
• pathogenesis
• prion
• transport

• Animals
• Central Nervous System/metabolism
• Peripheral Nervous System/metabolism
• PrPSc Proteins/chemistry
• Prion Diseases/metabolism
• Prions/chemistry

• R01 NS107246 NINDS NIH HHS
• 1R01NS107246 NIH HHS

Although prion infections cause cognitive impairment and neuronal death, transcriptional and translational profiling shows progressive derangement within glia but surprisingly little changes within neurons. Here we expressed PrP^C selectively in neurons and astrocytes of mice. After prion infection, both astrocyte and neuron‐restricted PrP^C expression led to copious brain accumulation of PrP^Sc. As expected, neuron‐restricted expression was associated with typical prion disease. However, mice with astrocyte‐restricted PrP^C expression experienced a normal life span, did not develop clinical disease, and did not show astro‐ or microgliosis. Besides confirming that PrP^Sc is innocuous to PrP^C‐deficient neurons, these results show that astrocyte‐born PrP^Sc does not activate the extreme neuroinflammation that accompanies the onset of prion disease and precedes any molecular changes of neurons. This points to a nonautonomous mechanism by which prion‐infected neurons instruct astrocytes and microglia to acquire a specific cellular state that, in turn, drives neural dysfunction.

• astrocytes
• neurons
• prions
• scrapie

Prion diseases are fatal neurodegenerative disorders with known natural occurrence in humans and a few other mammalian species. The diseases are experimentally transmissible, and the agent is derived from the host-encoded cellular prion protein (PrP^C), which is misfolded into a pathogenic conformer, designated PrP^Sc (scrapie). Aggregates of PrP^Sc molecules, constitute proteinaceous infectious particles, known as prions. Classical scrapie in sheep and goats and chronic wasting disease (CWD) in cervids are known to be infectious under natural conditions. In CWD, infected animals can shed prions via bodily excretions, allowing direct host-to-host transmission or indirectly via prion-contaminated environments. The robustness of prions means that transmission via the latter route can be highly successful and has meant that limiting the spread of CWD has proven difficult. In 2016, CWD was diagnosed for the first time in Europe, in reindeer (Rangifer tarandus) and European moose (Alces alces). Both were diagnosed in Norway, and, subsequently, more cases were detected in a semi-isolated wild reindeer population in the Nordfjella area, in which the first case was identified. This population was culled, and all reindeer (approximately 2400) were tested for CWD; 18 positive animals, in addition to the first diagnosed case, were found. After two years and around 25,900 negative tests from reindeer (about 6500 from wild and 19,400 from semi-domesticated) in Norway, a new case was diagnosed in a wild reindeer buck on Hardangervidda, south of the Nordfjella area, in 2020. Further cases of CWD were also identified in moose, with a total of eight in Norway, four in Sweden, and two cases in Finland. The mean age of these cases is 14.7 years, and the pathological features are different from North American CWD and from the Norwegian reindeer cases, resembling atypical prion diseases such as Nor98/atypical scrapie and H- and L-forms of BSE. In this review, these moose cases are referred to as atypical CWD. In addition, two cases were diagnosed in red deer (Cervus elaphus) in Norway. The emergence of CWD in Europe is a threat to European cervid populations, and, potentially, a food-safety challenge, calling for a swift, evidence-based response. Here, we review data on surveillance, epidemiology, and disease characteristics, including prion strain features of the newly identified European CWD agents.

• CWD
• Deer
• Fennoscandia
• Moose
• Nordic countries
• Prion disease
• Red deer
• Reindeer

• PrPSc
• TSE
• centrifugal
• centripetal
• nasal cavity
• olfactory system
• prion pathogenesis
• prionemia
• prions

• Animals
• Humans
• Nasal Cavity/pathology
• Nasal Mucosa/pathology
• Olfactory Pathways/pathology
• PrPSc Proteins/analysis
• Prion Diseases/pathology

• R01 NS061994 NINDS NIH HHS
• R01 NS107246 NINDS NIH HHS

• B-cell epitope
• Cellular prion protein (PrPc)
• immunoinformatics
• molecular dynamics simulation
• neurotoxicity

In prion diseases, the spread of infectious prions (PrPSc) is thought to occur within nerves and across synapses of the central nervous system (CNS). However, the mechanisms by which PrPSc moves within axons and across nerve synapses remain undetermined. Molecular motors, including kinesins and dyneins, transport many types of intracellular cargo. Kinesin-1C (KIF5C) has been shown to transport vesicles carrying the normal prion protein (PrPC) within axons, but whether KIF5C is involved in PrPSc axonal transport is unknown. The current study tested whether stereotactic inoculation in the striatum of KIF5C knock-out mice (Kif5c^−/−) with 0.5 µL volumes of mouse-adapted scrapie strains 22 L or ME7 would result in an altered rate of prion spreading and/or disease timing. Groups of mice injected with each strain were euthanized at either pre-clinical time points or following the development of prion disease. Immunohistochemistry for PrP was performed on brain sections and PrPSc distribution and tempo of spread were compared between mouse strains. In these experiments, no differences in PrPSc spread, distribution or survival times were observed between C57BL/6 and Kif5c^−/− mice.

• KIF5C
• PrP
• PrPC
• PrPSc
• kinesin
• prion
• scrapie

Somatic mutations arise postzygotically, producing genetic differences between cells in an organism. Well established as a driver of cancer, somatic mutations also exist in nonneoplastic cells, including in the brain. Technological advances in nucleic acid sequencing have enabled recent break-throughs that illuminate the roles of somatic mutations in aging and degenerative diseases of the brain. Somatic mutations accumulate during aging in human neurons, a process termed genosenium. A number of recent studies have examined somatic mutations in Alzheimer’s disease (AD), primarily from the perspective of genes causing familial AD. We have also gained new information on genome-wide mutations, providing insights into the cellular events driving somatic mutation and cellular dysfunction. This review highlights recent concepts, methods, and findings in the progress to understand the role of brain somatic mutation in aging and AD.

• Alzheimer's disease
• aging
• genomics
• mosaicism
• neurodegenerative diseases
• somatic mutation

• TDP43
• Tau
• amyloid-β
• neurodegeneration
• prion-like
• α-synuclein

• Humans
• Neurodegenerative Diseases/genetics
• Neurodegenerative Diseases/pathology
• Prion Diseases/genetics
• Prion Diseases/pathology
• Prion Proteins/genetics
• Proteostasis Deficiencies/genetics
• Proteostasis Deficiencies/pathology

• Department of Health
• National Institute for Health Research

• Molecular modeling
• PrP(Sc)
• Prion
• Prion diseases
• Protein structure

Prion diseases are fatal transmissible neurodegenerative conditions of humans and animals that arise through neurotoxicity induced by PrP misfolding. The cellular and molecular mechanisms of prion-induced neurotoxicity remain undefined. Understanding these processes will underpin therapeutic and control strategies for human and animal prion diseases, respectively. Prion diseases are difficult to study in their natural hosts and require the use of tractable animal models. Here we used RNA-Seq-based transcriptome analysis of prion-exposed Drosophila to probe the mechanism of prion-induced neurotoxicity. Adult Drosophila transgenic for pan neuronal expression of ovine PrP targeted to the plasma membrane exhibit a neurotoxic phenotype evidenced by decreased locomotor activity after exposure to ovine prions at the larval stage. Pathway analysis and quantitative PCR of genes differentially expressed in prion-infected Drosophila revealed up-regulation of cell cycle activity and DNA damage response, followed by down-regulation of eIF2 and mTOR signalling. Mitochondrial dysfunction was identified as the principal toxicity pathway in prion-exposed PrP transgenic Drosophila. The transcriptomic changes we observed were specific to PrP targeted to the plasma membrane since these prion-induced gene expression changes were not evident in similarly treated Drosophila transgenic for cytosolic pan neuronal PrP expression, or in non-transgenic control flies. Collectively, our data indicate that aberrant cell cycle activity, repression of protein synthesis and altered mitochondrial function are key events involved in prion-induced neurotoxicity, and correlate with those identified in mammalian hosts undergoing prion disease. These studies highlight the use of PrP transgenic Drosophila as a genetically well-defined tractable host to study mammalian prion biology.

• Drosophila melanogaster
• neurodegeneration
• prion
• transcriptomics

• Parkinson’s disease
• pathway
• prion-like propagation
• prionoid
• α-synuclein

The emergence of CWD in Europe in 2016 and the first natural infection in wild reindeer warranted disease management. This led to the testing of 2424 hunted or culled reindeer during 2016–2018, from the infected subpopulation in the Nordfjella mountain range in Southern Norway. To identify any association between PRNP variation and CWD susceptibility, we characterized the open reading frame of the PRNP gene in 19 CWD positive reindeer and in 101 age category- and sex-matched CWD negative controls. Seven variant positions were identified: 6 single nucleotide variants (SNVs) and a 24 base pair (bp) deletion located between nucleotide position 238 and 272, encoding four instead of five octapeptide repeats. With a single exception, all variant positions but one were predicted to be non-synonymous. The synonymous SNV and the deletion are novel in reindeer. Various combinations of the non-synonymous variant positions resulted in the identification of five PRNP alleles (A-E) that structured into 14 genotypes. We identified an increased CWD risk in reindeer carrying two copies of the most common allele, A, coding for serine in position 225 (Ser225) and in those carrying allele A together with the 24 bp deletion.

• CWD
• alleles
• deer
• disease management
• disease susceptibility
• gene frequency
• genotype
• prions
• reindeer
• risk

Cellular prion protein (PrP^C) is a membrane-anchored glycoprotein representing the physiological counterpart of PrP scrapie (PrP^Sc), which plays a pathogenetic role in prion diseases. Relatively little information is however available about physiological role of PrP^C. Although PrP^C ablation in mice does not induce lethal phenotypes, impairment of neuronal and bone marrow plasticity was reported in embryos and adult animals. In neurons, PrP^C stimulates neurite growth, prevents oxidative stress-dependent cell death, and favors antiapoptotic signaling. However, PrP^C activity is not restricted to post-mitotic neurons, but promotes cell proliferation and migration during embryogenesis and tissue regeneration in adult. PrP^C acts as scaffold to stabilize the binding between different membrane receptors, growth factors, and basement proteins, contributing to tumorigenesis. Indeed, ablation of PrP^C expression reduces cancer cell proliferation and migration and restores cell sensitivity to chemotherapy. Conversely, PrP^C overexpression in cancer stem cells (CSCs) from different tumors, including gliomas—the most malignant brain tumors—is predictive for poor prognosis, and correlates with relapses. The mechanisms of the PrP^C role in tumorigenesis and its molecular partners in this activity are the topic of the present review, with a particular focus on PrP^C contribution to glioma CSCs multipotency, invasiveness, and tumorigenicity.

• cancer stem cells
• cellular prion protein
• glioma
• intracellular signaling

• Animals
• Brain Neoplasms/drug therapy
• Brain Neoplasms/genetics
• Brain Neoplasms/metabolism
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Glioma/drug therapy
• Glioma/genetics
• Glioma/metabolism
• Humans
• Neoplasm Invasiveness
• Neoplastic Stem Cells/metabolism
• Nerve Regeneration
• PrPC Proteins/genetics
• PrPC Proteins/metabolism

• Aβ oligomers
• Ca2+ homeostasis
• Fyn
• NADPH oxidase
• ROS
• glutamate
• neurotransmission
• prion protein
• synapses

• Alzheimer Disease/metabolism
• Alzheimer Disease/pathology
• Amyloid beta-Peptides/metabolism
• Animals
• Calcium/metabolism
• Calcium Signaling
• Glutamic Acid/metabolism
• Humans
• Mitochondria/metabolism
• Mitochondria/pathology
• PrPC Proteins/metabolism
• Proto-Oncogene Proteins c-fyn/metabolism
• Reactive Oxygen Species/metabolism
• Receptors, Glutamate/metabolism

Alzheimer's disease (AD) and Parkinson's disease (PD) are age-associated neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn) and tau, respectively. The coexistence of aSyn and tau aggregates suggests a strong overlap between tauopathies and synucleinopathies. Interestingly, misfolded forms of aSyn and tau can propagate from cell to cell, and throughout the brain, thereby templating the misfolding of native forms of the proteins. The exact mechanisms involved in the propagation of the two proteins show similarities, and are reminiscent of the spreading characteristic of prion diseases. Recently, several models were developed to study the spreading of aSyn and tau. Here, we discuss the mechanisms involved, the similarities and differences between the spreading of the two proteins and that of the prion protein, and the different cell and animal models used for studying these processes. Ultimately, a deeper understanding of the molecular mechanisms involved may lead to the identification of novel targets for therapeutic intervention in a variety of devastating neurodegenerative diseases.

• Alzheimer's disease
• Parkinson's disease
• alpha-synuclein
• spreading
• tau

• aggregation
• amyloid
• prion
• propagation
• strain
• tau

• Cellular prion protein
• Eph
• HDAC
• Notch
• Prion infection

• Animals
• Epigenesis, Genetic
• Mice
• Neurons/metabolism
• Prion Diseases/genetics
• Prion Diseases/metabolism
• Prion Proteins/metabolism
• Receptors, Eph Family/metabolism
• Receptors, Notch/metabolism
• Signal Transduction/physiology

• Enteric nervous system
• Gut-brain axis
• Non-motor symptom
• Parkinson’s disease
• Prion-like
• α-synuclein

• 3’UTR
• BSE
• PRNP
• difference
• microRNA

• PrP(TSE)
• cerebrospinal fluid
• genetic CJD
• human prion diseases
• iatrogenic
• olfactory mucosa
• prion protein
• protein misfolding cyclic amplification
• real-time quaking-induced conversion
• sporadic CJD
• variant CJD

• Creutzfeldt–Jakob disease
• bovine spongiform encephalopathy
• chronic wasting disease
• immunomodulation
• mucosal immunization
• prion disease
• vaccine

• Animals
• Humans
• Immunomodulation/physiology
• Prion Diseases/immunology
• Prion Diseases/therapy
• Vaccination/methods

• immunotherapy
• luminescent polythiophene conjugates
• neurodegeneration
• prion
• therapeutics
• ubiquitin proteasome system

• Animals
• Blotting, Western
• Deer/metabolism
• Enzyme-Linked Immunosorbent Assay
• Epithelium/metabolism
• Gastrointestinal Tract/metabolism
• Immunohistochemistry
• Lymphoid Tissue/metabolism
• Nerve Tissue/metabolism
• Prion Proteins/metabolism
• Wasting Disease, Chronic/metabolism

• R01 AI112956 NIAID NIH HHS
• P01 AI077774 NIAID NIH HHS
• T32 OD010437 NIH HHS
• F30 OD021442 NIH HHS
• HHSN272201000009I NIAID NIH HHS
• R01 NS061902 NINDS NIH HHS
• National Institute of Neurological Disorders and Stroke
• NIH Office of the Director
• National Institute of Allergy and Infectious Diseases

Prion diseases are neurodegenerative conditions characterized by the conformational conversion of the cellular prion protein (PrP^C), an endogenous membrane glycoprotein of uncertain function, into PrP^Sc, a pathological isoform that replicates by imposing its abnormal folding onto PrP^C molecules. A great deal of evidence supports the notion that PrP^C plays at least two roles in prion diseases, by acting as a substrate for PrP^Sc replication, and as a mediator of its toxicity. This conclusion was recently supported by data suggesting that PrP^C may transduce neurotoxic signals elicited by other disease-associated protein aggregates. Thus, PrP^C may represent a convenient pharmacological target for prion diseases, and possibly other neurodegenerative conditions. Here, we sought to characterize the activity of chlorpromazine (CPZ), an antipsychotic previously shown to inhibit prion replication by directly binding to PrP^C. By employing biochemical and biophysical techniques, we provide direct experimental evidence indicating that CPZ does not bind PrP^C at biologically relevant concentrations. Instead, the compound exerts anti-prion effects by inducing the relocalization of PrP^C from the plasma membrane. Consistent with these findings, CPZ also inhibits the cytotoxic effects delivered by a PrP mutant. Interestingly, we found that the different pharmacological effects of CPZ could be mimicked by two inhibitors of the GTPase activity of dynamins, a class of proteins involved in the scission of newly formed membrane vesicles, and recently reported as potential pharmacological targets of CPZ. Collectively, our results redefine the mechanism by which CPZ exerts anti-prion effects, and support a primary role for dynamins in the membrane recycling of PrP^C, as well as in the propagation of infectious prions.

• Antipsychotic Agents/metabolism
• Antipsychotic Agents/pharmacology
• Cell Line
• Chlorpromazine/metabolism
• Chlorpromazine/pharmacology
• Dynamins/antagonists & inhibitors
• Humans
• Ligands
• Mutation
• Prion Proteins/genetics
• Prion Proteins/metabolism
• Protein Transport/drug effects

• Spain
• Italian Ministry of Health
• CJD Foundation
• E-Rare Joint Transnational Call
• Fondazione Telethon

The functions and mechanisms of prion proteins (PrP^C) are currently unknown, but most experts believe that deformed or pathogenic prion proteins (PrP^Sc) originate from PrP^C, and that there may be plural main sites for the conversion of normal PrP^C into PrP^Sc. In order to better understand the mechanism of PrP^C transformation to PrP^Sc, the most important step is to determine the replacement or substitution site.

BALB/c mice were challenged with prion RML strain and from 90 days post-challenge (dpc) mice were sacrificed weekly until all of them had been at 160 dpc. The ultra-structure and pathological changes of the brain of experimental mice were observed and recorded by transmission electron microscopy.

There were a large number of pathogen-like particles aggregated in the myelin sheath of the brain nerves, followed by delamination, hyperplasia, swelling, disintegration, phagocytic vacuolation, and other pathological lesions in the myelin sheath. The aggregated particles did not overflow from the myelin in unstained samples. The phenomenon of particle aggregation persisted all through the disease course, and was the earliest observed pathological change.

It was deduced that the myelin sheath and lipid rafts in brain nerves, including axons and dendrites, were the main sites for the conversion of PrP^C to PrP^Sc, and the PrP^Sc should be formed directly by the conversion of protein conformation without the involvement of nucleic acids.

• brain
• mice
• myelin sheath
• particle aggregation
• prion proteins

• ALS
• SOD1
• aggregates
• cranial nerves
• oligodendrocytes

• Animals
• Humans
• Models, Theoretical
• Prion Diseases

• National Institute for Health Research

• PrP
• Prion
• neurodegeneration

• Drosophila melanogaster
• PrP
• bioassay
• prion
• transmissible

Accidental transmission of prions during neurosurgery has been reported as a consequence of re-using contaminated surgical instruments. Several decontamination methods have been studied using the 263K-hamster prion; however, no studies have directly evaluated human prions. A newly developed in vitro amplification system, designated real-time quaking-induced conversion (RT-QuIC), has allowed the activity of abnormal prion proteins to be assessed within a few days. RT-QuIC using human recombinant prion protein (PrP) showed high sensitivity for prions as the detection limit of our assay was estimated as 0.12 fg of active prions. We applied this method to detect human prion activity on stainless steel wire. When we put wires contaminated with human Creutzfeldt–Jakob disease brain tissue directly into the test tube, typical PrP-amyloid formation was observed within 48 hours, and we could detect the activity of prions at 50% seeding dose on the wire from 10^2.8 to 10^5.8 SD₅₀. Using this method, we also confirmed that the seeding activities on the wire were removed following treatment with NaOH. As seeding activity closely correlated with the infectivity of prions using the bioassay, this wire-QuIC assay will be useful for the direct evaluation of decontamination methods for human prions.

Prion diseases are rare neurodegenerative conditions associated with the conformational conversion of the cellular prion protein (PrP^C) into PrP^Sc, a self-replicating isoform (prion) that accumulates in the central nervous system of affected individuals. The structure of PrP^Sc is poorly defined, and likely to be heterogeneous, as suggested by the existence of different prion strains. The latter represents a relevant problem for therapy in prion diseases, as some potent anti-prion compounds have shown strain-specificity. Designing therapeutics that target PrP^C may provide an opportunity to overcome these problems. PrP^C ligands may theoretically inhibit the replication of multiple prion strains, by acting on the common substrate of any prion replication reaction. Here, we characterized the properties of a cationic tetrapyrrole [Fe(III)-TMPyP], which was previously shown to bind PrP^C, and inhibit the replication of a mouse prion strain. We report that the compound is active against multiple prion strains in vitro and in cells. Interestingly, we also find that Fe(III)-TMPyP inhibits several PrP^C-related toxic activities, including the channel-forming ability of a PrP mutant, and the PrP^C-dependent synaptotoxicity of amyloid-β (Aβ) oligomers, which are associated with Alzheimer’s Disease. These results demonstrate that molecules binding to PrP^C may produce a dual effect of blocking prion replication and inhibiting PrP^C-mediated toxicity.

• Alzheimer's disease
• P301L tau
• neurodegeneration
• neurofibrillary tangles
• prion‐like

• BSE
• Buffalo
• Divergence
• Genetic differences
• PRNP
• Polymorphisms

Protein misfolding neurodegenerative diseases arise through neurotoxicity induced by aggregation of host proteins. These conditions include Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, motor neuron disease, tauopathies and prion diseases. Collectively, these conditions are a challenge to society because of the increasing aged population and through the real threat to human food security by animal prion diseases. It is therefore important to understand the cellular and molecular mechanisms that underlie protein misfolding-induced neurotoxicity as this will form the basis for designing strategies to alleviate their burden. Prion diseases are an important paradigm for neurodegenerative conditions in general since several of these maladies have now been shown to display prion-like phenomena. Increasingly, cell cycle activity and the DNA damage response are recognised as cellular events that participate in the neurotoxic process of various neurodegenerative diseases, and their associated animal models, which suggests they are truly involved in the pathogenic process and are not merely epiphenomena. Here we review the role of cell cycle activity and the DNA damage response in neurodegeneration associated with protein misfolding diseases, and suggest that these events contribute towards prion-induced neurotoxicity. In doing so, we highlight PrP transgenic Drosophila as a tractable model for the genetic analysis of transmissible mammalian prion disease.

• Neurodegenerative disease
• Protein misfolding
• Prion
• Transmissible
• Cell cycle
• DNA repair
• Chromatin
• PrP transgenic Drosophila

• NC/K000462/1 National Centre for the Replacement, Refinement and Reduction of Animals in Research

The physiological role of the cellular prion protein (PrP^C) is incompletely understood. The expression of PrP^C in hematopoietic stem cells and immune cells suggests a role in the development of these cells, and in PrP^C knockout animals altered immune cell proliferation and phagocytic function have been observed. Recently, a spontaneous nonsense mutation at codon 32 in the PRNP gene in goats of the Norwegian Dairy breed was discovered, rendering homozygous animals devoid of PrP^C. Here we report hematological and immunological analyses of homozygous goat kids lacking PrP^C (PRNP^Ter/Ter) compared to heterozygous (PRNP^+/Ter) and normal (PRNP^+/+) kids. Levels of cell surface PrP^C and PRNP mRNA in peripheral blood mononuclear cells (PBMCs) correlated well and were very low in PRNP^Ter/Ter, intermediate in PRNP^+/Ter and high in PRNP^+/+ kids. The PRNP^Ter/Ter animals had a shift in blood cell composition with an elevated number of red blood cells (RBCs) and a tendency toward a smaller mean RBC volume (P = 0.08) and an increased number of neutrophils (P = 0.068), all values within the reference ranges. Morphological investigations of blood smears and bone marrow imprints did not reveal irregularities. Studies of relative composition of PBMCs, phagocytic ability of monocytes and T-cell proliferation revealed no significant differences between the genotypes. Our data suggest that PrP^C has a role in bone marrow physiology and warrant further studies of PrP^C in erythroid and immune cell progenitors as well as differentiated effector cells also under stressful conditions. Altogether, this genetically unmanipulated PrP^C-free animal model represents a unique opportunity to unveil the enigmatic physiology and function of PrP^C.

• PrPC
• T-cell proliferation
• cellular prion protein
• hematology
• hematopoiesis
• phagocytosis

• Buffalo
• Dog
• Horse
• Low susceptibility
• PRNP
• Rabbit
• SPRN
• Transmissible spongiform encephalopathy

• Doppel
• Prnp−/− cell line
• Shadoo
• knockout mouse
• prion protein

• Neuroblasts
• Neurogenesis
• Neurosphere culture
• Proliferation
• Subventricular zone

Sporadic Creutzfeldt-Jakob disease is considered primarily a disease of grey matter, although the extent of white matter involvement has not been well described. We used diffusion tensor imaging to study the white matter in sporadic Creutzfeldt-Jakob disease compared to healthy control subjects and to correlated magnetic resonance imaging findings with histopathology. Twenty-six patients with sporadic Creutzfeldt-Jakob disease and nine age- and gender-matched healthy control subjects underwent volumetric T₁-weighted and diffusion tensor imaging. Six patients had post-mortem brain analysis available for assessment of neuropathological findings associated with prion disease. Parcellation of the subcortical white matter was performed on 3D T₁-weighted volumes using Freesurfer. Diffusion tensor imaging maps were calculated and transformed to the 3D-T₁ space; the average value for each diffusion metric was calculated in the total white matter and in regional volumes of interest. Tract-based spatial statistics analysis was also performed to investigate the deeper white matter tracts. There was a significant reduction of mean (P = 0.002), axial (P = 0.0003) and radial (P = 0.0134) diffusivities in the total white matter in sporadic Creutzfeldt-Jakob disease. Mean diffusivity was significantly lower in most white matter volumes of interest (P < 0.05, corrected for multiple comparisons), with a generally symmetric pattern of involvement in sporadic Creutzfeldt-Jakob disease. Mean diffusivity reduction reflected concomitant decrease of both axial and radial diffusivity, without appreciable changes in white matter anisotropy. Tract-based spatial statistics analysis showed significant reductions of mean diffusivity within the white matter of patients with sporadic Creutzfeldt-Jakob disease, mainly in the left hemisphere, with a strong trend (P = 0.06) towards reduced mean diffusivity in most of the white matter bilaterally. In contrast, by visual assessment there was no white matter abnormality either on T₂-weighted or diffusion-weighted images. Widespread reduction in white matter mean diffusivity, however, was apparent visibly on the quantitative attenuation coefficient maps compared to healthy control subjects. Neuropathological analysis showed diffuse astrocytic gliosis and activated microglia in the white matter, rare prion deposition and subtle subcortical microvacuolization, and patchy foci of demyelination with no evident white matter axonal degeneration. Decreased mean diffusivity on attenuation coefficient maps might be associated with astrocytic gliosis. We show for the first time significant global reduced mean diffusivity within the white matter in sporadic Creutzfeldt-Jakob disease, suggesting possible primary involvement of the white matter, rather than changes secondary to neuronal degeneration/loss.

Sporadic Creutzfeldt-Jakob disease (sCJD) is considered primarily a disease of grey matter. However, Caverzasi et al. now show a global decrease in mean diffusivity in white matter. The changes appear to be associated with reactive astrocytic gliosis and activated microglia, and suggest primary involvement of the white matter in sCJD.

• CJD
• DTI
• gliosis
• mean diffusivity
• microglia

• Aged
• Aged, 80 and over
• Anisotropy
• Creutzfeldt-Jakob Syndrome/pathology
• Demyelinating Diseases/pathology
• Diffusion Magnetic Resonance Imaging/methods
• Female
• Gray Matter/pathology
• Humans
• Image Processing, Computer-Assisted
• Male
• Middle Aged
• Nerve Fibers, Myelinated/pathology
• Neuroimaging
• White Matter/pathology

• K23 AG021989 NIA NIH HHS
• P50 AG023501 NIA NIH HHS
• AG021601 NIA NIH HHS
• P01 AG019724 NIA NIH HHS
• AG031220 NIA NIH HHS
• R01 AG-031189 NIA NIH HHS