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https://www.readbyqxmd.com/read/28646414/dynamic-meso-scale-anchorage-of-gpi-anchored-receptors-in-the-plasma-membrane-prion-protein-vs-thy1
#1
Yuri L Nemoto, Roger J Morris, Hiroko Hijikata, Taka A Tsunoyama, Akihiro C E Shibata, Rinshi S Kasai, Akihiro Kusumi, Takahiro K Fujiwara
The central mechanism for the transmission of the prion protein misfolding is the structural conversion of the normal cellular prion protein to the pathogenic misfolded prion protein, by the interaction with misfolded prion protein. This process might be enhanced due to the homo-dimerization/oligomerization of normal prion protein. However, the behaviors of normal prion protein in the plasma membrane have remained largely unknown. Here, using single fluorescent-molecule imaging, we found that both prion protein and Thy1, a control glycosylphosphatidylinositol-anchored protein, exhibited very similar intermittent transient immobilizations lasting for a few seconds within an area of 24...
June 24, 2017: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28646136/recurrent-background-mutations-in-whi2-impair-proteostasis-and-degradation-of-misfolded-cytosolic-proteins-in-saccharomyces-cerevisiae
#2
Sophie A Comyn, Stéphane Flibotte, Thibault Mayor
Proteostasis promotes viability at both the cellular and organism levels by maintaining a functional proteome. This requires an intricate protein quality control (PQC) network that mediates protein folding by molecular chaperones and removes terminally misfolded proteins via the ubiquitin proteasome system and autophagy. How changes within the PQC network can perturb proteostasis and shift the balance between protein folding and proteolysis remain poorly understood. However, given that proteostasis is altered in a number of conditions such as cancer and ageing, it is critical that we identify the factors that mediate PQC and understand the interplay between members of the proteostatic network...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28645531/new-protein-structures-provide-an-updated-understanding-of-phenylketonuria
#3
REVIEW
Eileen K Jaffe
Phenylketonuria (PKU) and less severe hyperphenylalaninemia (HPA) constitute the most common inborn error of amino acid metabolism, and is most often caused by defects in phenylalanine hydroxylase (PAH) function resulting in accumulation of Phe to neurotoxic levels. Despite the success of dietary intervention in preventing permanent neurological damage, individuals living with PKU clamor for additional non-dietary therapies. The bulk of disease-associated mutations are PAH missense variants, which occur throughout the entire 452 amino acid human PAH protein...
June 15, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28644434/ageing-and-hypoxia-cause-protein-aggregation-in-mitochondria
#4
Daniel M Kaufman, Xia Wu, Barbara A Scott, Omar A Itani, Marc R Van Gilst, James E Bruce, C Michael Crowder
Aggregation of cytosolic proteins is a pathological finding in disease states, including ageing and neurodegenerative diseases. We have previously reported that hypoxia induces protein misfolding in Caenorhabditis elegans mitochondria, and electron micrographs suggested protein aggregates. Here, we seek to determine whether mitochondrial proteins actually aggregate after hypoxia and other cellular stresses. To enrich for mitochondrial proteins that might aggregate, we performed a proteomics analysis on purified C...
June 23, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28643372/fine-tuning-perk-signaling-for-neuroprotection
#5
REVIEW
Mark Halliday, Daniel Hughes, Giovanna Mallucci
Protein translation and folding are tightly controlled processes in all cells, by proteostasis, an important component of which is the unfolded protein response (UPR). During periods of endoplasmic reticulum stress due to protein misfolding, the UPR activates a coordinated response in which the PERK branch activation restricts translation, while a variety of genes involved with protein folding, degradation, chaperone expression and stress responses are induced through signaling of the other branches. Chronic overactivation of the UPR, particularly the PERK branch is observed in the brains of patients in a number of protein misfolding neurodegenerative diseases, including Alzheimer's, and Parkinson's diseases and the taopathies...
June 23, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28642128/immunomodulation-of-parkinson-s-disease-using-mucuna-pruriens-mp
#6
REVIEW
Sachchida Nand Rai, Hareram Birla, Walia Zahra, Saumitra Sen Singh, Surya Pratap Singh
Immune control is associated with nigrostriatal neuroprotection for Parkinson's disease (PD); though its direct cause and effect relationships have not yet been realized and modulating the immune system for therapeutic gain has been openly discussed. While the pathobiology of PD remains in study, neuroinflammation is thought to speed nigrostriatal degeneration. The neuroinflammatory cascade associated with PD begins with aggregation of misfolded or post-translationally modified α-synuclein (α-syn). Such aggregation results in neuronal cell death and the presence of chronically activated glia (microglia and astroglia), leading to the production of proinflammatory cytokines like tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, and enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and cyclooxygenase-2 (COX-2)...
June 19, 2017: Journal of Chemical Neuroanatomy
https://www.readbyqxmd.com/read/28640595/detection-and-characterization-of-small-molecule-interactions-with-fibrillar-protein-aggregates-using-microscale-thermophoresis
#7
Emily Fisher, Yanyan Zhao, Robert Richardson, Malgorzata Janik, Alexander K Buell, Franklin I Aigbirhio, Gergely Toth
Neurodegenerative diseases such as Parkinson's and Alzheimer's disease share the pathological hallmark of fibrillar protein aggregates. The specific detection of these protein aggregates by positron emission tomography (PET) in the patient brain can yield valuable information for diagnosis and disease progression. However, the identification of novel small compounds that bind fibrillar protein aggregates has been a challenge. In this study, microscale thermophoresis (MST) was applied to assess the binding affinity of known small molecule ligands of α-synuclein fibrils, which were also tested in parallel in a Thioflavin T fluorescence competition assay for further validation...
June 22, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28640309/computational-analysis-of-histidine-mutations-on-the-structural-stability-of-human-tyrosinases-leading-to-albinism-insurgence
#8
Mubashir Hassan, Qamar Abbas, Hussain Raza, Ahmed A Moustafa, Sung-Yum Seo
Misfolding and structural alteration in proteins lead to serious malfunctions and cause various diseases in humans. Mutations at the active binding site in tyrosinase impair structural stability and cause lethal albinism by abolishing copper binding. To evaluate the histidine mutational effect, all mutated structures were built using homology modelling. The protein sequence was retrieved from the UniProt database, and 3D models of original and mutated human tyrosinase sequences were predicted by changing the residual positions within the target sequence separately...
June 22, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28634774/learning-from-synthetic-models-of-extracellular-matrix-differential-binding-of-wild-type-and-amyloidogenic-human-apolipoprotein-a-i-to-hydrogels-formed-from-molecules-having-charges-similar-to-those-found-in-natural-gags
#9
Silvana A Rosú, Leandro Toledo, Bruno F Urbano, Susana A Sanchez, Graciela C Calabrese, M Alejandra Tricerri
Among other components of the extracellular matrix (ECM), glycoproteins and glycosaminoglycans (GAGs) have been strongly associated to the retention or misfolding of different proteins inducing the formation of deposits in amyloid diseases. The composition of these molecules is highly diverse and a key issue seems to be the equilibrium between physiological and pathological events. In order to have a model in which the composition of the matrix could be finely controlled, we designed and synthesized crosslinked hydrophilic polymers, the so-called hydrogels varying the amounts of negative charges and hydroxyl groups that are prevalent in GAGs...
June 20, 2017: Protein Journal
https://www.readbyqxmd.com/read/28633019/edem-function-in-erad-protects-against-chronic-er-proteinopathy-and-age-related-physiological-decline-in-drosophila
#10
Michiko Sekiya, Akiko Maruko-Otake, Stephen Hearn, Yasufumi Sakakibara, Naoki Fujisaki, Emiko Suzuki, Kanae Ando, Koichi M Iijima
The unfolded protein response (UPR), which protects cells against accumulation of misfolded proteins in the ER, is induced in several age-associated degenerative diseases. However, sustained UPR activation has negative effects on cellular functions and may worsen disease symptoms. It remains unknown whether and how UPR components can be utilized to counteract chronic ER proteinopathies. We found that promotion of ER-associated degradation (ERAD) through upregulation of ERAD-enhancing α-mannosidase-like proteins (EDEMs) protected against chronic ER proteinopathy without inducing toxicity in a Drosophila model...
June 19, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28630454/treatment-with-a-non-toxic-self-replicating-anti-prion-delays-or-prevents-prion-disease-in-vivo
#11
R Diaz-Espinoza, R Morales, L Concha-Marambio, I Moreno-Gonzalez, F Moda, C Soto
Transmissible spongiform encephalopathies (TSEs) are fatal neurological disorders caused by prions, which are composed of a misfolded protein (PrP(Sc)) that self-propagates in the brain of infected individuals by converting the normal prion protein (PrP(C)) into the pathological isoform. Here, we report a novel experimental strategy for preventing prion disease based on producing a self-replicating, but innocuous PrP(Sc)-like form, termed anti-prion, which can compete with the replication of pathogenic prions...
June 20, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28629580/folding-underlies-bidirectional-role-of-gpr37-pael-r-in-parkinson-disease
#12
REVIEW
Lina Leinartaité, Per Svenningsson
Since conformational flexibility, which is required for the function of a protein, comes at the expense of structural stability, many proteins, including G-protein-coupled receptors (GPCRs), are under constant risk of misfolding and aggregation. In this regard GPR37 (also named PAEL-R and ETBR-LP-1) takes a prominent role, particularly in relation to Parkinson disease (PD). GPR37 is a substrate for parkin and accumulates abnormally in autosomal recessive juvenile parkinsonism, contributing to endoplasmic reticulum stress and death of dopaminergic neurons...
June 16, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28625912/isolation-of-recombinant-human-untagged-glyceraldehyde-3-phosphate-dehydrogenase-from-e-%C3%A2-coli-producer-strain
#13
K V Barinova, M A Eldarov, E V Khomyakova, V I Muronetz, E V Schmalhausen
The goal of the present work was expression of human glyceraldehyde-3-phosphate dehydrogenase (hGAPDH) without additional tag constructions in E. coli cells and elaboration of the procedure for purification of untagged hGAPDH from the extract of the producer cells. We present a simple method for purification of untagged hGAPDH including ammonium sulfate fractionation and gel filtration on a G-100 Sephadex column. The method allows isolation of 2 mg of pure hGAPDH from 600 ml of cell culture (7 g of the cell biomass)...
June 15, 2017: Protein Expression and Purification
https://www.readbyqxmd.com/read/28625364/semi-quantitative-models-for-identifying-potent-and-selective-transthyretin-amyloidogenesis-inhibitors
#14
Stephen Connelly, David E Mortenson, Sungwook Choi, Ian A Wilson, Evan T Powers, Jeffery W Kelly, Steven M Johnson
Rate-limiting dissociation of the tetrameric protein transthyretin (TTR), followed by monomer misfolding and misassembly, appears to cause degenerative diseases in humans known as the transthyretin amyloidoses, based on human genetic, biochemical and pharmacologic evidence. Small molecules that bind to the generally unoccupied thyroxine binding pockets in the native TTR tetramer kinetically stabilize the tetramer, slowing subunit dissociation proportional to the extent that the molecules stabilize the native state over the dissociative transition state-thereby inhibiting amyloidogenesis...
May 26, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28624654/insulin-signaling-an-opportunistic-target-to-minify-risk-of-alzheimer-s-disease
#15
REVIEW
Rohit Pardeshi, Nityanand Bolshette, Kundlik Gadhave, Ashutosh Ahire, Sahabuddin Ahmed, Tommaso Cassano, Veer Bala Gupta, Mangala Lahkar
Alzheimer's disease (AD) is progressive neurodegenerative disorder characterized by accumulation of senile plaques, neurofibrillary tangles (NFT) and neurodegeneration. The diabetes mellitus (DM) is one of the risk factors for AD pathogenesis by impairment in insulin signaling and glucose metabolism in central as well as peripheral system. Insulin resistance, impaired glucose and lipid metabolism lead to the Aβ (Aβ) aggregation, Tau phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, memory impairment and also mark over Aβ transport through central to peripheral and vice versa...
May 30, 2017: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/28623368/regulation-of-sub-compartmental-targeting-and-folding-properties-of-the-prion-like-protein-shadoo
#16
Anna Pepe, Rosario Avolio, Danilo Swann Matassa, Franca Esposito, Lucio Nitsch, Chiara Zurzolo, Simona Paladino, Daniela Sarnataro
Shadoo (Sho), a member of prion protein family, has been shown to prevent embryonic lethality in Prnp (0/0) mice and to be reduced in the brains of rodents with terminal prion diseases. Sho can also affect PrP structural dynamics and can increase the prion conversion into its misfolded isoform (PrP(Sc)), which is amyloidogenic and strictly related to expression, intracellular localization and association of PrP(C) to lipid rafts. We reasoned that if Sho possesses a natural tendency to convert to amyloid-like forms in vitro, it should be able to exhibit "prion-like" properties, such as PK-resistance and aggregation state, also in live cells...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28623285/structure-of-the-human-tric-cct-subunit-5-associated-with-hereditary-sensory-neuropathy
#17
Jose H Pereira, Ryan P McAndrew, Oksana A Sergeeva, Corie Y Ralston, Jonathan A King, Paul D Adams
The human chaperonin TRiC consists of eight non-identical subunits, and its protein-folding activity is critical for cellular health. Misfolded proteins are associated with many human diseases, such as amyloid diseases, cancer, and neuropathies, making TRiC a potential therapeutic target. A detailed structural understanding of its ATP-dependent folding mechanism and substrate recognition is therefore of great importance. Of particular health-related interest is the mutation Histidine 147 to Arginine (H147R) in human TRiC subunit 5 (CCT5), which has been associated with hereditary sensory neuropathy...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28622521/the-upr-er-sensor-and-coordinator-of-organismal-homeostasis
#18
REVIEW
Ashley E Frakes, Andrew Dillin
Life is stressful. Organisms are repeatedly exposed to stressors that disrupt protein homeostasis (proteostasis), resulting in protein misfolding and aggregation. To sense and respond to proteotoxic perturbations, cells have evolved compartment-specific stress responses, such as the unfolded protein response of the endoplasmic reticulum (UPR(ER)). However, UPR(ER) function is impaired with age, which, we propose, creates a permissive environment for protein aggregation, unresolved ER stress, and chronic inflammation...
June 15, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28622300/the-als-linked-e102q-mutation-in-sigma-receptor-1-leads-to-er-stress-mediated-defects-in-protein-homeostasis-and-dysregulation-of-rna-binding-proteins
#19
Alice Dreser, Jan Tilmann Vollrath, Antonio Sechi, Sonja Johann, Andreas Roos, Alfred Yamoah, Istvan Katona, Saeed Bohlega, Dominik Wiemuth, Yuemin Tian, Axel Schmidt, Jörg Vervoorts, Marc Dohmen, Cordian Beyer, Jasper Anink, Eleonora Aronica, Dirk Troost, Joachim Weis, Anand Goswami
Amyotrophic lateral sclerosis (ALS) is characterized by the selective degeneration of motor neurons (MNs) and their target muscles. Misfolded proteins which often form intracellular aggregates are a pathological hallmark of ALS. Disruption of the functional interplay between protein degradation (ubiquitin proteasome system and autophagy) and RNA-binding protein homeostasis has recently been suggested as an integrated model that merges several ALS-associated proteins into a common pathophysiological pathway...
June 16, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28622297/p53-mediated-suppression-of-bip-triggers-bik-induced-apoptosis-during-prolonged-endoplasmic-reticulum-stress
#20
Ignacio López, Anne-Sophie Tournillon, Rodrigo Prado Martins, Konstantinos Karakostis, Laurence Malbert-Colas, Karin Nylander, Robin Fåhraeus
Physiological and pathological conditions that affect the folding capacity of the endoplasmic reticulum (ER) provoke ER stress and trigger the unfolded protein response (UPR). The UPR aims to either restore the balance between newly synthesized and misfolded proteins or if the damage is severe, to trigger cell death. However, the molecular events underlying the switch between repair and cell death are not well understood. The ER-resident chaperone BiP governs the UPR by sensing misfolded proteins and thereby releasing and activating the three mediators of the UPR: PERK, IRE1 and ATF6...
June 16, 2017: Cell Death and Differentiation
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