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Prion Diseases

Ina Vorberg, Roberto Chiesa
Prion diseases are devastating neurodegenerative disorders for which no drugs are available. The successful development of therapeutics depends on drug screening platforms and preclinical models that recapitulate key molecular and pathological features of the disease. Innovative experimental tools have been developed over the last few years that might facilitate drug discovery, including cell-free prion replication assays and prion-infected flies. However, there is still room for improvement. Animal models of genetic prion disease are few, and only partially recapitulate the complexity of the human disorder...
March 13, 2019: Current Opinion in Pharmacology
Carlo Scialò, Elena De Cecco, Paolo Manganotti, Giuseppe Legname
Increasing evidence suggests that neurodegenerative disorders share a common pathogenic feature: the presence of deposits of misfolded proteins with altered physicochemical properties in the Central Nervous System. Despite a lack of infectivity, experimental data show that the replication and propagation of neurodegenerative disease-related proteins including amyloid-β (Aβ), tau, α-synuclein and the transactive response DNA-binding protein of 43 kDa (TDP-43) share a similar pathological mechanism with prions...
March 14, 2019: Viruses
Takeshi Fuchigami, Masao Kawasaki, Ryusuke Koyama, Mari Nakaie, Takehiro Nakagaki, Kazunori Sano, Ryuichiro Atarashi, Sakura Yoshida, Mamoru Haratake, Masahiro Ono, Noriyuki Nishida, Morio Nakayama
Prion diseases are fatal neurodegenerative disorders associated with the deposition of abnormal prion protein aggregates (PrPSc ) in the brain tissue. Here, we report the development of 125 I-labeled iodobenzofuran (IBF) derivatives as single photon emission computed tomography (SPECT) imaging probes to detect cerebral PrPSc deposits. We synthesized and radioiodinated several 5-IBF and 6-IBF derivatives. The IBF derivatives were evaluated as prion imaging probes using recombinant mouse prion protein (rMoPrP) aggregates and brain sections of mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice...
March 15, 2019: ACS Infectious Diseases
Heledd H Jarosz-Griffiths, Nicola J Corbett, Helen A Rowland, Kate Fisher, Alys C Jones, Jennifer Baron, Gareth J Howell, Sally A Cowley, Satyan Chintawar, M Zameel Cader, Katherine A B Kellett, Nigel M Hooper
The cellular prion protein (PrPC ) is a key neuronal receptor for amyloid-β oligomers (AβO), mediating their neurotoxicity, which contributes to the neurodegeneration in Alzheimer's disease (AD). Similarly to the amyloid precursor protein (APP), PrPC is proteolytically cleaved from the cell surface by a disintegrin and metalloprotease, ADAM10. We hypothesized that ADAM10-modulated PrPC shedding would alter the cellular binding and cytotoxicity of AβO. Here, we found that in human neuroblastoma cells, activation of ADAM10 with the muscarinic agonist carbachol promotes PrPC shedding and reduces the binding of AβO to the cell surface, which could be blocked with an ADAM10 inhibitor...
March 14, 2019: Journal of Biological Chemistry
Fabiana Miraglia, Emanuela Colla
Parkinson's Disease (PD) is typically classified as a neurodegenerative disease affecting the motor system. Recent evidence, however, has uncovered the presence of Lewy bodies in locations outside the CNS, in direct contact with the external environment, including the olfactory bulbs and the enteric nervous system. This, combined with the ability of alpha-synuclein (αS) to propagate in a prion-like manner, has supported the hypothesis that the resident microbial community, commonly referred to as microbiota, might play a causative role in the development of PD...
March 7, 2019: Cells
Paweł P Liberski, Agata Gajos, Beata Sikorska, Shirley Lindenbaum
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...
March 7, 2019: Viruses
Joseph B Rayman, Joud Hijazi, Xiang Li, Nancy Kedersha, Paul J Anderson, Eric R Kandel
TIA1 is a prion-related RNA-binding protein whose capacity to form various types of intracellular aggregates has been implicated in neurodegenerative disease. However, its role in normal brain function is poorly understood. Here, we show that TIA1 bidirectionally modulates stress-dependent synaptic plasticity in the hippocampus, a brain region involved in fear memory and olfactory discrimination learning. At the behavioral level, conditioned odor avoidance is potentiated by TIA1 deletion, whereas overexpression of TIA1 in the ventral hippocampus inhibits both contextual fear memory and avoidance...
March 12, 2019: Cell Reports
Dilshan S Harischandra, Dharmin Rokad, Matthew L Neal, Shivani Ghaisas, Sireesha Manne, Souvarish Sarkar, Nikhil Panicker, Gary Zenitsky, Huajun Jin, Mechelle Lewis, Xuemei Huang, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G Kanthasamy
The aggregation of α-synuclein (αSyn) is considered a key pathophysiological feature of certain neurodegenerative disorders, collectively termed synucleinopathies. Given that a prion-like, cell-to-cell transfer of misfolded αSyn has been recognized in the spreading of αSyn pathology in synucleinopathies, we investigated the biological mechanisms underlying the propagation of the disease with respect to environmental neurotoxic stress. Considering the potential role of the divalent metal manganese (Mn2+ ) in protein aggregation, we characterized its effect on αSyn misfolding and transmission in experimental models of Parkinson's disease...
March 12, 2019: Science Signaling
Brian S Appleby, Kathleen Glisic, Daniel D Rhoads, Alberto Bizzi, Mark L Cohen, Supriya Mahajan
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...
March 12, 2019: Dementia and Geriatric Cognitive Disorders
Alexandra Le Bras
No abstract text is available yet for this article.
March 11, 2019: Lab Animal
Dongjian Chen, Chao Huang, Jie Jin, Yue Wu, Zhuo Chen
Sulforaphane (SFN) is an active component extracted from vegetables like cauliflower and broccoli. Activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling is a common mechanism for the anti-oxidative and anti-inflammatory activity of some herb-derived compounds, such as icariin and berberine. However, due to its peculiar ability in Nrf2 activation, SFN is recognized as an activator of Nrf2 and recommended as a supplementation for prevention and/or treatment of disorders like neoplasm and heart failure...
March 8, 2019: European Journal of Pharmacology
Etienne Levavasseur, Nicolas Privat, Stéphane Haïk
Prions are atypical infectious agents lacking genetic material. Yet, various strains have been isolated from animals and humans using experimental models. They are distinguished by the resulting pattern of disease, including the localization of PrPsc deposits and the spongiform changes they induce in the brain of affected individuals. In this paper, we discuss the emerging use of cellular and acellular models to decipher the mechanisms involved in the strain-specific targeting of distinct brain regions. Recent studies suggest that neuronal cultures, protein misfolding cyclic amplification, and combination of both approaches may be useful to explore this under-investigated but central domain of the prion field...
March 9, 2019: Viruses
Colleen E D'Arcy, Ari Bitnun, Michael B Coulthart, Rolande D'Amour, Jeremy Friedman, J David Knox, Adam Rapoport, Snead Carter, Elysa Widjaja, Lili-Naz Hazrati, Gerard H Jansen
Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, fatal degenerative encephalopathy caused by a pathologically altered form of the prion protein (PrP). CJD is rare, with 1 and 2 cases per million per year reported in the general population, mostly in individuals over 50 years of age. It is almost unknown in the pediatric population. Sporadic CJD with unusually long survival (sCJD-LS), an unusual clinicopathological variant of CJD, has been described mostly in Japanese patients. We present here the first case report of pediatric CJD-LS occurring sporadically in a teenage girl of European descent, with initially rapid neurocognitive decline followed by a prolonged (∼10 years) clinical course...
March 11, 2019: Journal of Neuropathology and Experimental Neurology
Ali Chaari
Many neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, Prion's disease, polyQ and Huntington's disease share abnormal folding of potentially cytotoxic protein species associated with degeneration and death of specific neuronal populations. In order to maintain cellular protein homeostasis, neurons have developed an intrinsic protein quality control system as a strategy to counteract protein aggregation and their toxicity. Heat shock proteins are an essential component for regulating protein quality control and contribute potentially in the process of protein folding, prevent protein aggregation and in disaggregation in several neurodegenerative diseases...
March 7, 2019: International Journal of Biological Macromolecules
Surabhi Mehra, Shruti Sahay, Samir K Maji
α-Synuclein (α-Syn) has been extensively studied for its structural and biophysical properties owing to its pathophysiological role in Parkinson's disease. Lewy bodies and Lewy neurites are the pathological hallmarks of PD and contain α-Syn aggregates as their major component. Therefore, it was hypothesized that α-Syn aggregation is actively associated with Parkinson's disease pathogenesis. The central role of α-Syn aggregation in PD is further supported by the identification of point mutations in α-Syn protein associated with rare familial forms of PD...
March 7, 2019: Biochimica et Biophysica Acta. Proteins and Proteomics
Ruiying Yang, Kang Zou, Xiaohua Zhang, Cuicui Du, Jinhua Chen
As a significant biomarker of prion diseases, ultrasensitive assay of infectious isoform of prion (PrPSc ) is highly desirable for early diagnostics of prion diseases. Herein, taking normal cellular form of prion (PrPC ) as a model owing to a high risk of pathogenicity of PrPSc , a new photoelectrochemical immunosensor has been developed based on hemin-induced switching of photocurrent direction. In the presence of PrPC , nitrogen-doped porous carbon-hemin polyhedra labeled with secondary antibody were introduced onto the CdS-chitosan (CS) nanoparticles-modified indium-tin oxide (ITO) electrode via the antigen-antibody specific recognition...
February 21, 2019: Biosensors & Bioelectronics
S Pandya, Y Zeighami, B Freeze, M Dadar, D L Collins, A Dagher, A Raj
Growing evidence suggests that a "prion-like" mechanism underlies the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD). We extend and tailor previously developed quantitative and predictive network diffusion model (NDM) to PD, by specifically modeling the trans-neuronal spread of alpha-synuclein outward from the substantia nigra (SN). The model demonstrated the spatial and temporal patterns of PD from neuropathological and neuroimaging studies and was statistically validated using MRI deformation of 232 Parkinson's patients...
March 6, 2019: NeuroImage
Bension Shlomo Tilley, Colin Smith, Nicola Pavese, Johannes Attems
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disease that can mimic other neurological disorders. We present a case of sCJD in a 64-year-old man that presented with corticobasal syndrome and survived for 3 years. He presented initially with dementia, hemiparkinsonism and alien limb phenomenon and was diagnosed with corticobasal degeneration, ultimately progressing to immobility and akinetic mutism. With a normal MRI 1 year before onset, his neuroimaging 1 year later revealed abnormal DaTscan, cortical and hippocampal atrophy with ventricular dilatation on MRI, and diffusion-weighted cortical ribboning and thalamic hyperintensity...
March 7, 2019: BMJ Case Reports
Miren Aizpurua, Sashika Selvackadunco, Helen Yull, Christopher M Kipps, James W Ironside, Istvan Bodi
Sporadic prion diseases are fatal neurodegenerative disorders characterized clinically by rapidly progressive dementia and myoclonus. Variably protease-sensitive prionopathy (VPSPr) is a recently identified sporadic human prion disorder that may present with a lengthy atypical clinical history. Here, we describe a case of VPSPr in a patient with a long history of suspected frontotemporal dementia (FTD). A 61-year-old man presented with speech difficulties, including naming objects and constructing multipart sentences, while there was no difficulty in comprehension...
March 7, 2019: Neuropathology: Official Journal of the Japanese Society of Neuropathology
Alicia Otero, Carlos Hedman, Natalia Fernández-Borges, Hasier Eraña, Belén Marín, Marta Monzón, Manuel A Sánchez-Martín, Romolo Nonno, Juan José Badiola, Rosa Bolea, Joaquín Castilla
Specific variations in the amino acid sequence of prion protein (PrP) are key determinants of susceptibility to prion diseases. We previously showed that an amino acid substitution specific to canids confers resistance to prion diseases when expressed in mice and demonstrated its dominant-negative protective effect against a variety of infectious prion strains of different origins and characteristics. Here, we show that expression of this single amino acid change significantly increases survival time in transgenic mice expressing bank vole cellular prion protein (PrPC ), which is inherently prone to misfolding, following inoculation with two distinct prion strains (the CWD-vole strain and an atypical strain of spontaneous origin)...
March 7, 2019: Molecular Neurobiology
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