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Prion Diseases

Hye-Ju Han, Sokho Kim, Jungkee Kwon
Prion protein peptide (PrP) has been associated with neurotoxicity in brain cells and progression of prion diseases due to spongiform degeneration and accumulation of the infectious scrapie prion protein (PrPSc ). Autophagy has been shown to provide protective functions for neurodegenerative diseases, including prion disease. Thymosin beta 4 (Tβ4 ) plays a key role in the nervous system, providing a neuronal growth effect that includes motility, neurite outgrowth, and proliferation. However, the effect of Tβ4 on autophagy in prion disease has not been investigated...
December 15, 2018: Neurotoxicity Research
Julien Orts, Marielle Aulikki Wälti, Dhiman Ghosh, Silvia Campioni, Sven J Saupe, Roland Riek
Amyloid fibrils are pathological hallmark of various human diseases - including Parkinson's Alzheimer's, ALS, Prion diseases. Treatment of the amyloid diseases are hindered amongst other factors also due to timely detection and therefore, early detection of the amyloid fibrils would be beneficial for the treatment against these disorders. Here, we report a small molecular fluorescent probe that selectively recognize the fibrillar form of Amyloid beta(1-42), α-Synuclein, and HET-s(218-289) protein over their monomeric conformation...
December 11, 2018: Chembiochem: a European Journal of Chemical Biology
Soyoun Hwang, Trudy Tatum, Semakaleng Lebepe-Mazur, Eric M Nicholson
OBJECTIVE: Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative diseases, often referred as prion diseases. TSEs result from the misfolding of the cellular prion protein (PrPC ) into a pathogenic form (PrPSc ) that accumulates in the brain and lymphatic tissue. Amplification based assays such as real-time quaking induced conversion allow us to assess the conversion of PrPC to PrPSc . Real-time quaking induced conversion (RT-QuIC) can be used for the detection of PrPSc in a variety of biological tissues from humans and animals...
December 14, 2018: BMC Research Notes
Silvia A Purro, Mark A Farrow, Jacqueline Linehan, Tamsin Nazari, David X Thomas, Zhicheng Chen, David Mengel, Takashi Saito, Takaomi Saido, Peter Rudge, Sebastian Brandner, Dominic M Walsh, John Collinge
We previously reported1 the presence of amyloid-β protein (Aβ) deposits in individuals with Creutzfeldt-Jakob disease (CJD) who had been treated during childhood with human cadaveric pituitary-derived growth hormone (c-hGH) contaminated with prions. The marked deposition of parenchymal and vascular Aβ in these relatively young individuals with treatment-induced (iatrogenic) CJD (iCJD), in contrast to other prion-disease patients and population controls, allied with the ability of Alzheimer's disease brain homogenates to seed Aβ deposition in laboratory animals, led us to argue that the implicated c-hGH batches might have been contaminated with Aβ seeds as well as with prions...
December 13, 2018: Nature
Leeanne McGurk, Edward Gomes, Lin Guo, James Shorter, Nancy Bonini
TAR DNA-binding protein of 43 kDa (TDP-43) forms granulo-filamentous aggregates in affected brain regions of >95% of patients with ALS and ~50% of patients with frontotemporal degeneration (FTD). Furthermore, in disease, TDP-43 becomes N-terminally truncated resulting in protein deposits that are mainly composed of the C-terminal prion-like domain (PrLD). The PrLD is inherently aggregation-prone and is hypothesized to drive protein aggregation of TDP-43 in disease. Here, we establish that the N-terminal region of the protein is critical for rapid TDP-43 granulo-filamentous aggregation...
December 12, 2018: Biochemistry
Julie-Myrtille Bourgognon, Joern R Steinert
Neurodegenerative disorders are often associated with cellular dysfunction caused by underlying protein-misfolding signalling. Numerous neuropathologies are diagnosed at late stage symptomatic changes which occur in response to these molecular malfunctions and treatment is often too late or restricted only to the slowing of further cell death. Important new strategies to identify early biomarkers with predictive value to intervene with disease progression at stages where cell dysfunction has not progressed irreversibly is of paramount importance...
March 2019: Neural Regeneration Research
Xinhai Zhang, Saied Mirshahidi, Chien-Shing Chen
Biobanks are facilities that collect, process, store, annotate, and distribute high-quality and well-maintained human biological specimens (biospecimens) for investigational use. They play a crucial role in biomarker research and contribute to our understanding about preventing, diagnosing, and treating diseases. Majority of the biospecimens are from patients volunteering to provide biospecimens that would normally be discarded after diagnostic or therapeutic procedures. Potential pathogens in collected biospecimens may contaminate the instruments and work space, leaving the personnel at risk of being infected...
2019: Methods in Molecular Biology
Sayed Sartaj Sohrab, Mohd Suhail, Ashraf Ali, Mohammad Amjad Kamal, Azamal Husen, Fahim Ahmad, Esam Ibraheem Azhar, Nigel H Greig
Dementia is known as loss of cellular communications in the brain at a region caused by multi-factorial diseases and pathogenic infections. Approximately eighty percent reported cases of Alzheimer's disease are followed by vascular dementia. The common symptoms of dementia include memory loss, concentration problems, thinking, and language solving situations. Dementia is a multifactorial disease but based on latest research; various reports have been published describing the linkage and role of viruses, prions and miRNAs in neurodegeneration and neurodegenerative disorders resulting into dementia and due to this we selected to review and provide latest information related to dementia...
December 2018: Virusdisease
Matthew J Fogarty
The synapse is an incredibly specialized structure that allows for the coordinated communication of information from one neuron to another. When assembled into circuits, steady streams of excitatory and inhibitory synaptic activity shape neural outputs. At the organismal level, ensembles of neural networks underlie behavior, emotion and memory. Disorder or dysfunctions of synapses, a synaptopathy, may underlie a host of developmental and degenerative neurological conditions. There is a possibility that amyotrophic lateral sclerosis may be a result of a synaptopathy within the neuromotor system...
February 2019: Neural Regeneration Research
Cristian Bonvicini, Catia Scassellati, Luisa Benussi, Emilio Di Maria, Carlo Maj, Miriam Ciani, Silvia Fostinelli, Anna Mega, Martina Bocchetta, Gaetana Lanzi, Edoardo Giacopuzzi, Sergio Ferraboli, Michela Pievani, Virginia Fedi, Carlo Alberto Defanti, Silvia Giliani, Giovanni Battista Frisoni, Roberta Ghidoni, Massimo Gennarelli
BACKGROUND: Early onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia. OBJECTIVE: To identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E (APOE) and prion protein (PRNP) genes were also assessed. METHODS: We studied 22 EOD patients recruited in Memory Clinics, in the context of studies investigating genetic forms of dementia...
December 3, 2018: Journal of Alzheimer's Disease: JAD
Ewa Laskowska, Dorota Kuczyńska-Wiśnik, Barbara Lipińska
Protein homeostasis (proteostasis) refers to the ability of cells to preserve the correct balance between protein synthesis, folding and degradation. Proteostasis is essential for optimal cell growth and survival under stressful conditions. Various extracellular and intracellular stresses including heat shock, oxidative stress, proteasome malfunction, mutations and aging-related modifications can result in disturbed proteostasis manifested by enhanced misfolding and aggregation of proteins. To limit protein misfolding and aggregation cells have evolved various strategies including molecular chaperones, proteasome system and autophagy...
December 6, 2018: Journal of Proteomics
Andrew G B Thompson, Simon H Mead
The human prion diseases are a diverse set of often rapidly progressive neurodegenerative conditions associated with abnormal forms of the prion protein. We review work to establish diagnostic biomarkers and assays that might fill other important roles, particularly those that could assist the planning and interpretation of clinical trials. The field now benefits from highly sensitive and specific diagnostic biomarkers using cerebrospinal fluid: detecting by-products of rapid neurodegeneration or specific functional properties of abnormal prion protein, with the second generation real time quaking induced conversion (RT-QuIC) assay being particularly promising...
December 4, 2018: Molecular and Cellular Neurosciences
Apurwa M Sharma, Talitha L Thomas, DaNae R Woodard, Omar M Kashmer, Marc I Diamond
Tauopathies have diverse presentation, progression, and neuropathology. They are linked to tau prion strains, self-replicating assemblies of unique quaternary conformation, whose origin is unknown. Strains can be propagated indefinitely in cultured cells, and induce unique patterns of transmissible neuropathology upon inoculation into mice. DS9 and DS10 cell lines propagate different synthetic strains that derive from recombinant tau. We previously observed that tau monomer adopts two conformational states: one that is inert (Mi ) and one that is seed-competent (Ms ) (Mirbaha et al...
December 11, 2018: ELife
Guoxin Zhang, Yun Xia, Fang Wan, Kai Ma, Xingfang Guo, Liang Kou, Sijia Yin, Chao Han, Ling Liu, Jinsha Huang, Nian Xiong, Tao Wang
Parkinson's disease (PD) is one of the synucleinopathies spectrum of disorders typified by the presence of intraneuronal protein inclusions. It is primarily composed of misfolded and aggregated forms of alpha-synuclein (α-syn), the toxicity of which has been attributed to the transition from an α-helical conformation to a β-sheetrich structure that polymerizes to form toxic oligomers. This could spread and initiate the formation of "LB-like aggregates," by transcellular mechanisms with seeding and subsequent permissive templating...
2018: Frontiers in Aging Neuroscience
Fakhra Amin, Bilqees Bano
Thiol Protease inhibitors (cystatins) are endogenous natural inhibitors of cysteine proteases. They are present in all mammalians cells and body fluids. Cystatin are allocated into three major families. Family -I stefins, family -II cystatins and family -III kininogens, according to their amino acid sequence, molecular weight, carbohydrate content and disulphide bonds. It has been investigated that thiol proteases (cathepsin) and their endogenous inhibitor, cystatins have been closely associated with diseases like Alzheimer's, Prions, neurodegenerative diseases, cancer and diabetes...
December 3, 2018: International Journal of Biological Macromolecules
Brian S Appleby, Allyson Connor, Han Wang
Human prion diseases are usually rapid neurodegenerative illnesses that are invariably fatal. Despite several clinical trials, no effective treatment has been discovered in humans. Although prior clinical trials have not been successful, they provided information that is vital for the formation of future clinical trials. Among these findings is the realization that there are several prion disease-specific aspects that must be considered when conducting clinical trials. The rarity, rapidity, and clinical heterogeneity of prion disease affect study enrollment and the ability to measure treatment effects...
November 30, 2018: Current Opinion in Pharmacology
Alsu Kuznetsova, Catherine Cullingham, Debbie McKenzie, Judd M Aiken
Chronic wasting disease (CWD), an environmentally transmissible, fatal prion disease is endemic in North America, present in South Korea and has recently been confirmed in northern Europe. The expanding geographic range of this contagious disease of free-ranging deer, moose, elk and reindeer has resulted in increasing levels of prion infectivity in the environment. Soils are involved in CWD horizontal transmission, acting as an environmental reservoir, and soil mineral and organic compounds have the ability to bind prions...
November 2018: PLoS Pathogens
Annika Keller, Mario Nuvolone, Irina Abakumova, Andra Chincisan, Regina Reimann, Merve Avar, Daniel Heinzer, Simone Hornemann, Josephin Wagner, Daniel Kirschenbaum, Fabian F Voigt, Caihong Zhu, Luca Regli, Fritjof Helmchen, Adriano Aguzzi
Transmissible spongiform encephalopathies (TSEs) are caused by the prion, which consists essentially of PrPSc, an aggregated, conformationally modified form of the cellular prion protein (PrPC). Although TSEs can be experimentally transmitted by intracerebral inoculation, most instances of infection in the field occur through extracerebral routes. The epidemics of kuru and variant Creutzfeldt-Jakob disease were caused by dietary exposure to prions, and parenteral administration of prion-contaminated hormones has caused hundreds of iatrogenic TSEs...
November 2018: PLoS Pathogens
Kohtaro Miyazawa, Kentaro Masujin, Yuichi Matsuura, Yoshifumi Iwamaru, Takashi Yokoyama, Hiroyuki Okada
In animal prion diseases, including bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease in cervids, and scrapie in sheep and goats, a disease-associated isoform of prion protein (PrPd ) accumulates in the brains of affected animals. Although the CH1641 scrapie isolate was experimentally established in the UK, a few natural CH1641-like scrapie cases have been reported in France and the UK. The molecular mass of the unglycosylated protease-resistant core of PrPd (PrPres) is known to be similar between CH1641-like scrapie and experimental BSE in sheep...
November 28, 2018: Veterinary Research
Paul A De Sousa, Diane Ritchie, Alison Green, Siddharthan Chandran, Richard Knight, Mark W Head
The inadvertent transmission of long incubating, untreatable and fatal neurodegenerative prionopathies, notably iatrogenic Creutzfeldt-Jakob disease, following transplantation of cadaver-derived corneas, pituitary growth, hormones and dura mater, constitutes a historical precedent which has underpinned the application of precautionary principles to modern day advanced cell therapies. To date these have been reflected by geographic or medical history risk-based deferral of tissue donors. Emergent understanding of other prion-like proteinopathies, their potential independence from prions as a transmissible agent and the variable capability of scalably manufacturable stem cells and derivatives to take up and clear or to propagate prions, substantiate further commitment to qualifying neurodegenerative proteinopathy transmission risks...
November 27, 2018: Acta Neuropathologica
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