• Familial prion disease
• Nonsense mutations
• Prion protein
• Q159X
• Toxicity

• Animals
• Brain/pathology
• Brain/metabolism
• Humans
• Prion Diseases/genetics
• Prion Diseases/pathology
• Prion Diseases/metabolism
• Mice
• Prion Proteins/genetics
• Prion Proteins/metabolism
• Mutation/genetics
• Mutant Proteins/metabolism
• Gliosis/pathology
• Gliosis/genetics
• Animals, Newborn
• Mice, Inbred C57BL
• Prions/metabolism
• Prions/genetics

• E200K
• PrP
• PrPSc
• genetic prion disease
• iPSC
• neurodegeneration
• prion
• prion disease
• synapse

• Induced Pluripotent Stem Cells/metabolism
• Induced Pluripotent Stem Cells/cytology
• Humans
• Creutzfeldt-Jakob Syndrome/genetics
• Creutzfeldt-Jakob Syndrome/pathology
• Creutzfeldt-Jakob Syndrome/metabolism
• Neurons/metabolism
• Neurons/pathology
• Synapses/metabolism
• Synapses/pathology
• Female
• Mutation
• Male
• Prion Proteins/genetics
• Prion Proteins/metabolism
• Cell Differentiation/genetics
• Pedigree
• Adult
• Middle Aged
• Receptors, N-Methyl-D-Aspartate/metabolism
• Receptors, N-Methyl-D-Aspartate/genetics
• PrPSc Proteins/metabolism
• PrPSc Proteins/genetics

• Animals
• Cattle
• Humans
• Creutzfeldt-Jakob Syndrome/diagnosis
• Creutzfeldt-Jakob Syndrome/genetics
• Creutzfeldt-Jakob Syndrome/pathology
• Prion Proteins/metabolism
• Prion Diseases/diagnosis
• Prion Diseases/genetics
• Prion Diseases/metabolism
• Brain/pathology

• automatic washer
• electrolyzed water
• endoscope

• Humans
• Disinfection/methods
• Detergents
• Feasibility Studies
• RNA, Ribosomal, 16S
• Equipment Contamination/prevention & control
• Endoscopes/microbiology

• clinical characteristics
• creutzfeldt-jakob disease
• electroencephalography
• magnetic resonance imaging
• periodic sharp wave complexes

• Creutzfeldt–Jakob disease
• Diagnosis
• Epidemiology
• Prion
• RT-QuIC

• Humans
• Creutzfeldt-Jakob Syndrome/diagnosis
• Creutzfeldt-Jakob Syndrome/epidemiology
• Prospective Studies
• Pandemics
• Sensitivity and Specificity
• COVID-19

• 1369-341 Robert-Koch-Institute

• Alzheimer's disease
• Intraocular injection
• Neurofibrillary tangles
• Retina
• Tau pathology propagation
• Transgenic mouse

• Animals
• Humans
• Neurodegenerative Diseases
• Primates
• Prion Diseases/metabolism
• Prion Proteins
• Prions/metabolism

• R01 NS125255 NINDS NIH HHS
• National Institutes of Health
• Prion Alliance
• Broad Institute
• Ono Pharma Foundation
• Anonymous Organization

Amyotrophic lateral sclerosis (ALS) is the third most frequent neurodegenerative disease after Alzheimer’s and Parkinson’s disease. ALS is characterized by the selective and progressive loss of motoneurons in the spinal cord, brainstem and cerebral cortex. Clinical manifestations typically occur in midlife and start with focal muscle weakness, followed by the rapid and progressive wasting of muscles and subsequent paralysis. As with other neurodegenerative diseases, the condition typically begins at an initial point and then spreads along neuroanatomical tracts. This feature of disease progression suggests the spreading of prion-like proteins called prionoids in the affected tissues, which is similar to the spread of prion observed in Creutzfeldt-Jakob disease. Intensive research over the last decade has proposed the ALS-causing gene products Cu/Zn superoxide dismutase 1, TAR DNA-binding protein of 43 kDa, and fused in sarcoma as very plausible prionoids contributing to the spread of the pathology. In this review, we will discuss the molecular and cellular mechanisms leading to the propagation of these prionoids in ALS.

• amyotrophic lateral sclerosis
• physiopathology
• prion-like
• protein aggregation
• therapy

• Extracellular vesicle
• Neurotoxicity
• Prion disease

• Alzheimer’s disease
• amyloid
• cerebral amyloid angiopathy
• diagnostic
• early diagnosis
• eye
• fluorophore
• neurodegeneration
• prion
• protein misfolding
• retina
• retinal amyloid

• Alzheimer Disease/metabolism
• Amyloid beta-Peptides/metabolism
• Amyloidogenic Proteins/metabolism
• Amyloidosis
• Animals
• Cerebral Amyloid Angiopathy/metabolism
• Longitudinal Studies
• Mice
• Neurodegenerative Diseases
• Prion Diseases/diagnostic imaging
• Prion Diseases/metabolism
• Prions/metabolism
• Retina/diagnostic imaging
• Retina/metabolism

• RF1 NS121992 NINDS NIH HHS
• R01 NS069566 NINDS NIH HHS
• R37 NS076896 NINDS NIH HHS
• R01 NS076896 NINDS NIH HHS
• P30 AG066530 NIA NIH HHS
• K99 AG061251 NIA NIH HHS
• R01 NS121992 NINDS NIH HHS
• R21 NS110409 NINDS NIH HHS
• RF1 AG062362 NIA NIH HHS
• R43 AG057421 NIA NIH HHS

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 (PrP^Sc), defining two major PrP^Sc 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 PrP^Sc 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 PrP^Sc 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 PrP^Sc 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.

• CJD subtypes
• FFI
• Fatal familial insomnia
• PRNP
• Prion disease
• Prion protein
• Prion strains

• Brain/metabolism
• Glycosylation
• Humans
• Phenotype
• Prion Diseases/metabolism
• Prions

We previously reported a phenotype of Creutzfeldt-Jakob disease (CJD), CJD-MMiK, that could help identify iatrogenic CJD. To find cases mimicking CJD-MMiK, we investigated clinical features and pathology of 1,155 patients with diagnosed sporadic CJD or unclassified CJD with and without history of neurosurgery. Patients with history of neurosurgery more frequently had an absence of periodic sharp-wave complexes on electroencephalogram than patients without a history of neurosurgery. Among 27 patients with history of neurosurgery, 5 had no periodic sharp-wave complexes on electroencephalogram. We confirmed 1 case of CJD-MMiK and suspected another. Both had methionine homozygosity at codon 129 of the prion protein gene and hyperintensity lesions in the thalamus on magnetic resonance images of the brain, which might be a clinical marker of CJD-MMiK. A subgroup with a history of neurosurgery and clinical features mimicking dura mater graft-associated CJD might have been infected during neurosurgery and had symptoms develop after many years.

• Creutzfeldt-Jakob disease
• diffusion-weight magnetic resonance imaging
• iatrogenic transmission
• neurosurgery
• prions,
• thalamus

• Creutzfeldt-Jakob Syndrome/etiology
• Creutzfeldt-Jakob Syndrome/genetics
• Humans
• Iatrogenic Disease
• Neurosurgery
• Prion Proteins/genetics
• Prions

Fatal Familial Insomnia (FFI) is a genetic prion disease caused by the D178N mutation in the prion protein gene (PRNP) in coupling phase with methionine at PRNP 129. In 2017, we have shown that the olfactory mucosa (OM) collected from FFI patients contained traces of PrPSc detectable by Protein Misfolding Cyclic Amplification (PMCA).

In this work, we have challenged PMCA-generated products obtained from OM and brain homogenate of FFI patients in BvPrP-Tg407 transgenic mice expressing the bank vole prion protein to test their ability to induce prion pathology.

All inoculated mice developed mild spongiform changes, astroglial activation, and PrPSc deposition mainly affecting the thalamus. However, their neuropathological alterations were different from those found in the brain of BvPrP-Tg407 mice injected with raw FFI brain homogenate.

Although with some experimental constraints, we show that PrPSc present in OM of FFI patients is potentially infectious.

This work was supported in part by the Italian Ministry of Health (GR-2013-02355724 and Ricerca Corrente), MJFF, ALZ, Alzheimer’s Research UK and the Weston Brain Institute (BAND2015), and Euronanomed III (SPEEDY) to FM; by the Spanish Ministerio de Economía y Competitividad (grant AGL2016-78054-R [AEI/FEDER, UE]) to JMT and JCE; AM-M was supported by a fellowship from the INIA (FPI-SGIT-2015-02).

• fatal familial insomnia
• medicine
• mouse
• neurodegeneration
• neuroscience
• olfactory mucosa
• prion
• protein misfolding cyclic amplification
• transmission studies

The absence of an adequate animal model for studies has limited the understanding of congenital Zika syndrome (CZS) in humans during the outbreak in America. In this study, we used squirrel monkeys (Saimiri collinsi), a neotropical primate (which mimics the stages of human pregnancy), as a model of Zika virus (ZIKV) infection. Seven pregnant female squirrel monkeys were experimentally infected at three different gestational stages, and we were able reproduce a broad range of clinical manifestations of ZIKV lesions observed in newborn humans. Histopathological and immunohistochemical analyses of early-infected newborns (2/4) revealed damage to various areas of the brain and ZIKV antigens in the cytoplasm of neurons and glial cells, indicative of CZS. The changes caused by ZIKV infection were intrauterine developmental delay, ventriculomegaly, simplified brain gyri, vascular impairment and neuroprogenitor cell dysfunction. Our data show that the ZIKV infection outcome in squirrel monkeys is similar to that in humans, indicating that this model can be used to help answer questions about the effect of ZIKV infection on neuroembryonic development and the morphological changes induced by CZS.

Sporadic Creutzfeldt-Jakob disease (sCJD) is the commonest human prion disease, occurring most likely as the consequence of spontaneous formation of abnormal prion protein in the central nervous system (CNS). Variant Creutzfeldt–Jakob disease (vCJD) is an acquired prion disease that was first identified in 1996. In marked contrast to vCJD, previous investigations in sCJD revealed either inconsistent levels or an absence of PrP^Sc in peripheral tissues. These findings contributed to the consensus that risks of transmitting sCJD as a consequence of non-CNS invasive clinical procedures were low. In this study, we systematically measured prion infectivity levels in CNS and peripheral tissues collected from vCJD and sCJD patients. Unexpectedly, prion infectivity was detected in a wide variety of peripheral tissues in sCJD cases. Although the sCJD infectivity levels varied unpredictably in the tissues sampled and between patients, these findings could impact on our perception of the possible transmission risks associated with sCJD.

• Adult
• Aged
• Aged, 80 and over
• Animals
• Creutzfeldt-Jakob Syndrome/transmission
• Female
• Humans
• Male
• Mice
• Middle Aged
• PrPSc Proteins

• Directorate-General for International Cooperation and Development (BE)
• Food Standards Agency
• Seventh Framework Programme
• Department of Health(GB)
• the Scottish Government
• Medical Research Council (GB)

• Huntingtin
• Huntington’s disease-like
• Prion-like
• Tissue spongiform encephalopathies

• Alzheimer’s disease
• amyloid-beta
• iatrogenic
• neurodegenerative diseases
• prion disease
• prion-like
• protein misfolding
• transmission

• Alzheimer Disease/metabolism
• Alzheimer Disease/physiopathology
• Amyloid beta-Peptides/metabolism
• Animals
• Brain/physiopathology
• Creutzfeldt-Jakob Syndrome/metabolism
• Creutzfeldt-Jakob Syndrome/physiopathology
• Humans
• Mice
• Neurodegenerative Diseases/metabolism
• Neurodegenerative Diseases/physiopathology
• Phenotype
• Plaque, Amyloid
• Prion Diseases/metabolism
• Prion Diseases/physiopathology
• Prion Proteins/metabolism
• Prions/metabolism
• Protein Denaturation
• Protein Folding
• alpha-Synuclein/metabolism
• tau Proteins/metabolism

During the Zika virus (ZIKV) outbreak in Brazil (2015–2016), the clinical manifestations associated with its infection were complex and included miscarriage and congenital malformations, not previously described. In this study, we evaluated the prenatal conditions of pregnant female squirrel monkeys (Saimiri collinsi) infected during different gestational thirds (GTs) and assessed all clinical aspects, diagnostic imaging, viremia and the immune response. In our study, 75% of the infected animals in the 1st GT group had significant clinical manifestations, such as miscarriage and prolonged viremia associated with a late immune response. Consequently, their neonates showed fetal neuropathology, such as cerebral hemorrhage, lissencephaly or malformations of the brain grooves, ventriculomegaly, and craniofacial malformations. Thus, our study demonstrated the relevance of pregnant squirrel monkeys as a model for the study of ZIKV infection in neonates due to the broad clinical manifestations presented, including the typical congenital Zika syndrome manifestations described in humans.

• Atrophy
• CJD
• DTI
• JCD
• Jakob-Creutzfeldt
• Mean diffusivity
• Prion

• Atrophy/pathology
• Brain/diagnostic imaging
• Brain/pathology
• Creutzfeldt-Jakob Syndrome/diagnostic imaging
• Creutzfeldt-Jakob Syndrome/pathology
• Diffusion Magnetic Resonance Imaging
• Disease Progression
• Gray Matter/pathology
• Humans
• Magnetic Resonance Imaging

• UL1 RR024131 NCRR NIH HHS
• P01 AG019724 NIA NIH HHS
• R01 AG031189 NIA NIH HHS
• K23 AG059888 NIA NIH HHS
• R01 AG062562 NIA NIH HHS
• K23 AG061253 NIA NIH HHS
• P50 AG023501 NIA NIH HHS
• K24 AG045333 NIA NIH HHS
• R37 AG031220 NIA NIH HHS

The normal cellular isoform of prion protein, designated PrP^C, is constitutively converted to the abnormally folded, amyloidogenic isoform, PrP^Sc, in prion diseases, which include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. PrP^C is a membrane glycoprotein consisting of the non-structural N-terminal domain and the globular C-terminal domain. During conversion of PrP^C to PrP^Sc, its 2/3 C-terminal region undergoes marked structural changes, forming a protease-resistant structure. In contrast, the N-terminal region remains protease-sensitive in PrP^Sc. Reverse genetic studies using reconstituted PrP^C-knockout mice with various mutant PrP molecules have revealed that the N-terminal domain has an important role in the normal function of PrP^C and the conversion of PrP^C to PrP^Sc. The N-terminal domain includes various characteristic regions, such as the positively charged residue-rich polybasic region, the octapeptide repeat (OR) region consisting of five repeats of an octapeptide sequence, and the post-OR region with another positively charged residue-rich polybasic region followed by a stretch of hydrophobic residues. We discuss the normal functions of PrP^C, the conversion of PrP^C to PrP^Sc, and the neurotoxicity of PrP^Sc by focusing on the roles of the N-terminal regions in these topics.

• neurodegeneration
• prion
• prion disease
• prion protein
• protein conformation

• Animals
• Humans
• Mutation
• Prion Diseases/genetics
• Prion Diseases/metabolism
• Prion Proteins/chemistry
• Prion Proteins/genetics
• Prion Proteins/metabolism
• Protein Conformation
• Protein Domains

• Cofactor
• Cofactor selection
• Mammalian
• Phosphatidylethanolamine
• Phospholipid
• Polyanion
• Prion
• RNA
• Specific infectivity

• Animals
• Catalysis
• Humans
• Models, Biological
• PrPSc Proteins/metabolism
• Prions/chemistry
• Prions/isolation & purification
• Prions/metabolism
• Prions/pathogenicity

• R01 NS102301 NINDS NIH HHS
• R01 NS117276 NINDS NIH HHS
• R01 NS118796 NINDS NIH HHS

The detection of prion seeding activity in CSF and olfactory mucosal brushings using real‐time quaking‐induced conversion assays allows highly accurate clinical diagnosis of sporadic Creutzfeldt–Jakob disease. To gauge transmission risks associated with these biospecimens and their testing, we have bioassayed prion infectivity levels in patients’ brain tissue, nasal brushings, and CSF, and assessed the pathogenicity of amplified products of real‐time quaking‐induced conversion assays seeded with Creutzfeldt–Jakob disease prions.

We obtained olfactory mucosal brushings and CSF from patients with a final diagnosis of sporadic Creutzfeldt–Jakob disease subtype MM1 (n = 3). Samples were inoculated intracerebrally into Tg66 transgenic mice that overexpress the homologous human 129M prion protein. The mice were evaluated for clinical, neuropathological, and biochemical evidence of prion infection.

Patients’ brain tissue at 10² to 10⁵ fold dilutions affected 47/48 Tg66 mice. In contrast, maximum acutely tolerable doses of insoluble pellets from their olfactory mucosa brushings caused evidence of prion disease in only 4/28 inoculated mice, and no effects were seen with 10‐fold dilutions. No clinical prion disease was observed in mice inoculated with antemortem CSF samples or prion‐seeded real‐time quaking‐induced conversion assay products.

Pellets from patients’ olfactory mucosa brushings had ≥10,000‐fold lower infectivity per unit volume than brain tissue, while CSF lacked detectable infectivity. Nonetheless, the results suggest that appropriate precautions may be warranted in surgical interventions involving the olfactory areas. The lack of pathogenic infectivity in the real‐time quaking‐induced conversion assay products provides evidence that the assay does not replicate biohazardous prions in vitro.

In the human prion disease Creutzfeldt-Jakob disease (CJD), different CJD neuropathological subtypes are defined by the presence in normal prion protein (PrP^C) of a methionine or valine at residue 129, by the molecular mass of the infectious prion protein PrP^Sc, by the pattern of PrP^Sc deposition, and by the distribution of spongiform change in the brain. Heterozygous cases of CJD potentially add another layer of complexity to defining CJD subtypes since PrP^Sc can have either a methionine (PrP^Sc-M129) or valine (PrP^Sc-V129) at residue 129. We have recently demonstrated that the relative amount of PrP^Sc-M129 versus PrP^Sc-V129, i.e. the PrP^Sc allotype ratio, varies between heterozygous CJD cases. In order to determine if differences in PrP^Sc allotype correlated with different disease phenotypes, we have inoculated 10 cases of heterozygous CJD (7 sporadic and 3 iatrogenic) into two transgenic mouse lines overexpressing PrP^C with a methionine at codon 129. In one case, brain-region specific differences in PrP^Sc allotype appeared to correlate with differences in prion disease transmission and phenotype. In the other 9 cases inoculated, the presence of PrP^Sc-V129 was associated with plaque formation but differences in PrP^Sc allotype did not consistently correlate with disease incubation time or neuropathology. Thus, while the PrP^Sc allotype ratio may contribute to diverse prion phenotypes within a single brain, it does not appear to be a primary determinative factor of disease phenotype.

• CJD
• Creutzfeldt-Jakob disease
• PrPSc allotype
• Prion

Transmissible spongiform encephalopathies or prion diseases are rapidly progressive neurodegenerative diseases, the clinical manifestation of which can resemble other promptly evolving neurological maladies. Therefore, the unequivocal ante-mortem diagnosis is highly challenging and was only possible by histopathological and immunohistochemical analysis of the brain at necropsy. Although surrogate biomarkers of neurological damage have become invaluable to complement clinical data and provide more accurate diagnostics at early stages, other neurodegenerative diseases show similar alterations hindering the differential diagnosis. To solve that, the detection of the pathognomonic biomarker of disease, PrP^Sc, the aberrantly folded isoform of the prion protein, could be used. However, the amounts in easily accessible tissues or body fluids at pre-clinical or early clinical stages are extremely low for the standard detection methods. The solution comes from the recent development of in vitro prion propagation techniques, such as Protein Misfolding Cyclic Amplification (PMCA) and Real Time-Quaking Induced Conversion (RT-QuIC), which have been already applied to detect minute amounts of PrP^Sc in different matrixes and make early diagnosis of prion diseases feasible in a near future. Herein, the most relevant tissues and body fluids in which PrP^Sc has been detected in animals and humans are being reviewed, especially those in which cell-free prion propagation systems have been used with diagnostic purposes.

• PMCA
• PrPSc
• RT-QuIC
• diagnostic
• prion disease
• transmissible spongiform encephalopathy

• Anti-prion therapy
• Prion disease
• Prion strains

• Alzheimer’s disease
• amyotrophic lateral sclerosis
• biomarker
• multiple sclerosis
• neurodegeneration
• optical coherence tomography
• parkinson’s disease
• prion disease
• retina

• amyloid
• amyloid-β
• infectivity
• pathogenesis
• prion
• synuclein
• tau
• transmission

• Alzheimer Disease/etiology
• Alzheimer Disease/metabolism
• Alzheimer Disease/pathology
• Amyloid/chemistry
• Amyloid/metabolism
• Animals
• Humans
• Membrane Proteins/metabolism
• Parkinson Disease/etiology
• Parkinson Disease/metabolism
• Parkinson Disease/pathology
• Prion Diseases/metabolism
• Prion Diseases/pathology
• Prion Diseases/transmission
• Prions/metabolism
• Prions/pathogenicity
• Protein Aggregates
• Protein Folding
• Scrapie/etiology
• Scrapie/metabolism
• Synucleins/metabolism
• Virulence

• Intramural Research Program of the NIAID Intramural NIH HHS

• Clinical phenotype
• Creutzfeldt-Jakob disease
• Heidenhain variant
• early diagnosis
• human prions
• movement disorders
• neurodegenerative dementia
• seizures

• Creutzfeldt–Jakob disease
• GSS
• VPSPr
• experimental transmission
• fatal insomnia
• human prion disease
• prion
• strain

• Biological Variation, Population
• Genetic Variation
• Humans
• Prion Diseases/pathology
• Prion Diseases/physiopathology
• Prion Proteins/chemistry
• Prion Proteins/classification
• Prion Proteins/genetics
• Prion Proteins/metabolism
• Protein Aggregates
• Protein Conformation

Degeneration of photoreceptors in the retina is a major cause of blindness in humans. Often retinal degeneration is due to inheritance of mutations in genes important in photoreceptor (PR) function, but can also be induced by other events including retinal trauma, microvascular disease, virus infection or prion infection. The onset of apoptosis and degeneration of PR neurons correlates with invasion of the PR cellular areas by microglia or monocytes, suggesting a causal role for these cells in pathogenesis of PR degenerative disease. To study the role of microglia in prion-induced retinal disease, we fed prion-infected mice a CSF-1 receptor blocking drug, PLX5622, to eliminate microglia in vivo, and the effects on retinal degeneration were analyzed over time. In mice not receiving drug, the main inflammatory cells invading the degenerating PR areas were microglia, not monocytes. Administration of PLX5622 was highly effective at ablating microglia in retina. However, lack of microglia during prion infection did not prevent degeneration of PR cells. Therefore, microglia were not required for the PR damage process during prion infection. Indeed, mice lacking microglia had slightly faster onset of PR damage. Similar results were seen in C57BL/10 mice and transgenic mice expressing GFP or RFP on microglia and monocytes, respectively. These results were supported by experiments using prion-infected Cx3cr1 knockout mice without PLX5622 treatment, where microglial expansion in retina was delayed, but PR degeneration was not. Contrary to predictions, microglia were not a causative factor in retinal damage by prion infection. Instead, newly generated PrPSc accumulated around the inner segment region of the PR cells and appeared to correlate with initiation of the pathogenic process in the absence of microglia.

• Cx3cr1 knockout
• Degeneration
• Gliosis
• Macrophages
• Microglia
• Müller cells
• PLX5622
• Photoreceptors
• Prion protein
• Prions
• Retina
• Scrapie

• neurodegeneration
• prion
• prion-like proteins
• strains

• Amyloid beta-Peptides/genetics
• Animals
• DNA-Binding Proteins
• Disease Models, Animal
• Humans
• Mice
• Neurodegenerative Diseases/pathology
• Prion Proteins/genetics
• Prions/genetics
• Prions/pathogenicity
• Protein Folding
• tau Proteins/genetics

Kuru, the first human prion disease was transmitted to chimpanzees by D. Carleton Gajdusek (1923–2008). In this review, we summarize the history of this seminal discovery, its anthropological background, epidemiology, clinical picture, neuropathology, and molecular genetics. We provide descriptions of electron microscopy and confocal microscopy of kuru amyloid plaques retrieved from a paraffin-embedded block of an old kuru case, named Kupenota. The discovery of kuru opened new vistas of human medicine and was pivotal in the subsequent transmission of Creutzfeldt–Jakob disease, as well as the relevance that bovine spongiform encephalopathy had for transmission to humans. The transmission of kuru was one of the greatest contributions to biomedical sciences of the 20th century.

• Carleton Gajdusek
• Kuru
• neuropathology
• prion diseases

• Animals
• Arvicolinae
• Communicable Diseases
• Mammals
• PrPC Proteins/metabolism
• PrPC Proteins/physiology
• PrPSc Proteins/metabolism
• PrPSc Proteins/pathogenicity
• PrPSc Proteins/physiology
• Prion Proteins/metabolism
• Prion Proteins/physiology
• Prions/metabolism
• Prions/pathogenicity
• Prions/physiology
• Protein Processing, Post-Translational

• R21 NS095763 NINDS NIH HHS
• T32 AI007519 NIAID NIH HHS
• R56 NS094576 NINDS NIH HHS
• R01 NS102301 NINDS NIH HHS
• R21 NS099928 NINDS NIH HHS
• R01 NS118796 NINDS NIH HHS
• National Institutes of Health

• Creutzfeldt-Jakob disease
• Gerstmann-Sträussler-Scheinker disease
• amyloidosis
• fatal insomnia
• human prions
• neurodegenerative dementia
• prion strains

• Disease heterogeneity
• PrP(Sc)
• Prion
• Survival
• Therapy

• Biomarker
• Blood
• CJD
• CSF
• NFL
• Prion
• RT-QuIC
• Tau

• Creutzfeldt-Jakob disease
• RT-QuIC
• eye
• prion

• Aged
• Autopsy
• Brain/pathology
• Creutzfeldt-Jakob Syndrome/pathology
• Eye/pathology
• Female
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Prion Diseases/diagnosis
• Prions/isolation & purification
• Retina/pathology

• R01 NS069566 NINDS NIH HHS
• R37 NS076896 NINDS NIH HHS
• R01 NS076896 NINDS NIH HHS
• R56 AG055619 NIA NIH HHS
• R01 AG031189 NIA NIH HHS
• R01 NS088485 NINDS NIH HHS
• R21 NS110409 NINDS NIH HHS
• R21 NS105498 NINDS NIH HHS
• ZIA AI001086 Intramural NIH HHS
• Equity in Brain Health at Global Brain Health Institute
• HHS | National Institutes of Health (NIH)
• Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID)

• CJD
• Creutzfeldt-Jakob disease
• Jakob-Creutzfeldt disease
• Protein misfolding disorders
• Rapidly progressive dementia
• Transmissible spongiform encephalopathies

• Animals
• Humans
• Prion Diseases

• R21 AG068757 NIA NIH HHS
• R56 AG055619 NIA NIH HHS
• L30 AG024892 NIA NIH HHS
• R01 AG031189 NIA NIH HHS
• K23 AG021989 NIA NIH HHS

• CJD
• CSF
• MRI
• biomarker
• codon 129
• dementia
• diagnosis
• molecular subtypes
• neuropathology
• prion

• Age Distribution
• Brain/metabolism
• Brain/pathology
• Creutzfeldt-Jakob Syndrome/epidemiology
• Creutzfeldt-Jakob Syndrome/genetics
• Creutzfeldt-Jakob Syndrome/mortality
• Creutzfeldt-Jakob Syndrome/physiopathology
• Humans
• Mutation/genetics
• Prion Proteins/genetics

• Mass spectrometry
• Prion inactivation
• Proteomics

• P01 AI106705 NIAID NIH HHS
• R01 NS083687 NINDS NIH HHS
• T32 NS091006 NINDS NIH HHS

• Exosomes
• Extracellular vesicles
• Multivesicular bodies
• Prion diseases
• Protein aggregation

• Animals
• Extracellular Vesicles/metabolism
• Humans
• Nanotubes
• PrPC Proteins/metabolism
• PrPSc Proteins/metabolism
• Prion Diseases/etiology
• Prions/metabolism
• Protein Aggregates
• Protein Folding
• Protein Transport

• CWD strains
• RT-QuIC
• barrier
• chronic wasting disease
• cross-species transmission
• cynomolgus macaques
• prion
• squirrel monkeys

• Brain/pathology
• Humans
• Magnetic Resonance Imaging
• Mutation
• Prion Diseases/genetics
• Prion Diseases/pathology
• Prion Proteins/genetics
• Prion Proteins/metabolism