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https://www.readbyqxmd.com/read/28899654/deciphering-the-loss-of-metal-binding-due-to-mutation-d83g-of-human-sod1-protein-causing-fals-disease
#1
E Srinivasan, R Rajasekaran
Mutations in Cu/Zn superoxide dismutase 1 (SOD1) protein are found to be the causative factor, behind the majority of familial amyotrophic later sclerosis (FALS) cases. The mutations particularly on the metal (Zn) binding residues are found to increase the disease onset in the individuals suffering from FALS, while the presence of the metal ion (Zn) is essential for the catalytic activity and retaining the protein stability. Thus in our study, we focused on one such metal binding mutant (D83G) and assessed the impact of the mutation on protein structure and function...
September 9, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28884318/implications-of-fals-mutations-on-sod1-function-and-oligomerization-in-cell-models
#2
Aline A Brasil, Rayne S S Magalhães, Mariana D C De Carvalho, Isabel Paiva, Ellen Gerhardt, Marcos D Pereira, Tiago F Outeiro, Elis C A Eleutherio
Among the familial forms of amyotrophic lateral sclerosis (fALS), 20% are associated with the Cu,Zn-superoxide dismutase (Sod1). fALS is characterized by the accumulation of aggregated proteins and the increase in oxidative stress markers. Here, we used the non-invasive bimolecular fluorescence complementation (BiFC) assay in human H4 cells to investigate the kinetics of aggregation and subcellular localization of Sod1 mutants. We also studied the effect of the different Sod1 mutants to respond against oxidative stress by following the levels of reactive oxygen species (ROS) after treatment with hydrogen peroxide...
September 7, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28877271/spinal-cord-homogenates-from-sod1-familial-amyotrophic-lateral-sclerosis-induce-sod1-aggregation-in-living-cells
#3
Edward Pokrishevsky, Ran Ha Hong, Ian R Mackenzie, Neil R Cashman
Mutant Cu/Zn superoxide dismutase (SOD1) can confer its misfolding on wild-type SOD1 in living cells; the propagation of misfolding can also be transmitted between cells in vitro. Recent studies identified fluorescently-tagged SOD1G85R as a promiscuous substrate that is highly prone to aggregate by a variety of templates, in vitro and in vivo. Here, we utilized several SOD1-GFP reporter proteins with G37R, G85R, or G93A mutations in SOD1. We observed that human spinal cord homogenates prepared from SOD1 familial ALS (FALS) can induce significantly more intracellular reporter protein aggregation than spinal cord homogenates from sporadic ALS, Alzheimer's disease, multiple system atrophy or healthy control individuals...
2017: PloS One
https://www.readbyqxmd.com/read/28864422/als-linked-mutant-sod1-proteins-promote-a%C3%AE-aggregates-in-als-through-direct-interaction-with-a%C3%AE
#4
Ja-Young Jang, Hyungmin Cho, Hye-Yoon Park, Hyangshuk Rhim, Seongman Kang
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motor neurons. Aggregation of ALS-linked mutant Cu/Zn superoxide dismutase (SOD1) is a hallmark of a subset of familial ALS (fALS). Recently, intracellular amyloid-β (Aβ) is detected in motor neurons of both sporadic and familial ALS. We have previously shown that intracellular Aβ specifically interacts with G93A, an ALS-linked SOD1 mutant. However, little is known about the pathological and biological effect of this interaction in neurons...
August 30, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28832631/dna-strand-breaks-and-tdp-43-mislocation-are-absent-in-the-murine-hsod1g93a-model-of-amyotrophic-lateral-sclerosis-in-vivo-and-in-vitro
#5
Diane Penndorf, Vedrana Tadić, Otto W Witte, Julian Grosskreutz, Alexandra Kretz
Mutations in the human Cu/Zn superoxide dismutase type-1 (hSOD1) gene are common in familial amyotrophic lateral sclerosis (fALS). The pathophysiology has been linked to, e.g., organelle dysfunction, RNA metabolism and oxidative DNA damage conferred by SOD1 malfunction. However, apart from metabolically evoked DNA oxidation, it is unclear whether severe genotoxicity including DNA single-strand breaks (SSBs) and double-strand breaks (DSBs), originates from loss of function of nuclear SOD1 enzyme. Factors that endogenously interfere with DNA integrity and repair complexes in hSOD1-mediated fALS remain similarly unexplored...
2017: PloS One
https://www.readbyqxmd.com/read/28801801/nuclear-envelope-a-new-frontier-in-plant-mechanosensing
#6
REVIEW
Kateryna Fal, Atef Asnacios, Marie-Edith Chabouté, Olivier Hamant
In animals, it is now well established that forces applied at the cell surface are propagated through the cytoskeleton to the nucleus, leading to deformations of the nuclear structure and, potentially, to modification of gene expression. Consistently, altered nuclear mechanics has been related to many genetic disorders, such as muscular dystrophy, cardiomyopathy and progeria. In plants, the integration of mechanical signals in cell and developmental biology has also made great progress. Yet, while the link between cell wall stresses and cytoskeleton is consolidated, such cortical mechanical cues have not been integrated with the nucleoskeleton...
August 12, 2017: Biophysical Reviews
https://www.readbyqxmd.com/read/28768772/a-computational-combinatorial-approach-identifies-a-protein-inhibitor-of-superoxide-dismutase-1-misfolding-aggregation-and-cytotoxicity
#7
Victor Banerjee, Ofek Oren, Efrat Ben-Zeev, Ran Taube, Stanislav Engel, Niv Papo
Molecular agents that specifically bind and neutralize misfolded and toxic superoxide dismutase 1 (SOD1) mutant proteins may find application in attenuating the disease progression of familial amyotrophic lateral sclerosis (fALS). However, high structural similarities between the wild-type and mutant SOD1 proteins limit the utility of this approach. Here, we addressed this challenge by converting a promiscuous natural human IgG binding domain, the hyperthermophilic variant of protein G (HTB1), into a highly specific aggregation inhibitor (designated HTB1M) of two fALS-linked SOD1 mutants, SOD1G93A and SOD1G85R...
August 2, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28744320/quantification-of-tumor-vascular-permeability-and-blood-volume-by-positron-emission-tomography
#8
Haojun Chen, Xiao Tong, Lixin Lang, Orit Jacobson, Bryant C Yung, Xiangyu Yang, Ruiliang Bai, Dale O Kiesewetter, Ying Ma, Hua Wu, Gang Niu, Xiaoyuan Chen
Purpose: Evans Blue (EB) is an azo dye that binds quantitatively with serum albumin. With an albumin binding, NOTA conjugated truncated Evan's blue (NEB) dye derived PET tracer, we aimed to establish a strategy for evaluating vascular permeability in malignant tumors via non-invasive PET. Experimental design: Sixty-minute dynamic PET using [(18)F]FAl-NEB was performed in three xenograft tumor models including INS-1 rat insulinoma, UM-SCC-22B human head and neck carcinoma and U-87 MG human glioblastoma. Tumor vascular permeability was quantified by the difference of the slopes between tumor and blood time-activity curve (TACs, expressed as Ps )...
2017: Theranostics
https://www.readbyqxmd.com/read/28709720/burden-of-rare-variants-in-als-genes-influences-survival-in-familial-and-sporadic-als
#9
Shirley Yin-Yu Pang, Jacob Shujui Hsu, Kay-Cheong Teo, Yan Li, Michelle H W Kung, Kathryn S E Cheah, Danny Chan, Kenneth M C Cheung, Miaoxin Li, Pak-Chung Sham, Shu-Leong Ho
Genetic variants are implicated in the development of amyotrophic lateral sclerosis (ALS), but it is unclear whether the burden of rare variants in ALS genes has an effect on survival. We performed whole genome sequencing on 8 familial ALS (FALS) patients with superoxide dismutase 1 (SOD1) mutation and whole exome sequencing on 46 sporadic ALS (SALS) patients living in Hong Kong and found that 67% had at least 1 rare variant in the exons of 40 ALS genes; 22% had 2 or more. Patients with 2 or more rare variants had lower probability of survival than patients with 0 or 1 variant (p = 0...
June 20, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28680390/the-role-of-the-heat-shock-protein-b8-hspb8-in-motoneuron-diseases
#10
REVIEW
Paola Rusmini, Riccardo Cristofani, Mariarita Galbiati, Maria E Cicardi, Marco Meroni, Veronica Ferrari, Giulia Vezzoli, Barbara Tedesco, Elio Messi, Margherita Piccolella, Serena Carra, Valeria Crippa, Angelo Poletti
Amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA) are two motoneuron diseases (MNDs) characterized by aberrant protein behavior in affected cells. In familial ALS (fALS) and in SBMA specific gene mutations lead to the production of neurotoxic proteins or peptides prone to misfold, which then accumulate in form of aggregates. Notably, some of these proteins accumulate into aggregates also in sporadic ALS (sALS) even if not mutated. To prevent proteotoxic stresses detrimental to cells, misfolded and/or aggregated proteins must be rapidly removed by the protein quality control (PQC) system...
2017: Frontiers in Molecular Neuroscience
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
#11
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...
October 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28621357/computational-investigation-of-the-human-sod1-mutant-cys146arg-that-directs-familial-amyotrophic-lateral-sclerosis
#12
E Srinivasan, R Rajasekaran
The genetic substitution mutation of Cys146Arg in the SOD1 protein is predominantly found in the Japanese population suffering from familial amyotrophic lateral sclerosis (FALS). A complete study of the biophysical aspects of this particular missense mutation through conformational analysis and producing free energy landscapes could provide an insight into the pathogenic mechanism of ALS disease. In this study, we utilized general molecular dynamics simulations along with computational predictions to assess the structural characterization of the protein as well as the conformational preferences of monomeric wild type and mutant SOD1...
July 25, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28607591/pet-of-her2-expression-with-a-novel-18-fal-labeled-affibody
#13
Yuping Xu, Zhicheng Bai, Qianhuan Huang, Yunyun Pan, Donghui Pan, Lizhen Wang, Junjie Yan, Xinyu Wang, Runlin Yang, Min Yang
Background: Human epidermal growth factor receptor type 2 (HER2) is abundant in a wide variety of tumors and associated with the poor prognosis. Radiolabeled affibodies are potential candidates for detecting HER2-positive lesions. However, laborious multiple-step synthetic procedure and high abdomen background may hinder the widespread use. Herein, cysteinylated ZHER2:342 modified with a new hydrophilic linker (denoted as MZHER2:342) was designed and labeled using (18)FAl-NOTA strategies. The biologic efficacy of the novel tracer and its feasibilities for in vivo monitoring HER2 levels were also investigated in xenograft models with different HER2 expressions...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28596251/hypothalamic-atrophy-is-related-to-body-mass-index-and-age-at-onset-in-amyotrophic-lateral-sclerosis
#14
Martin Gorges, Pauline Vercruysse, Hans-Peter Müller, Hans-Jürgen Huppertz, Angela Rosenbohm, Gabriele Nagel, Patrick Weydt, Åsa Petersén, Albert C Ludolph, Jan Kassubek, Luc Dupuis
OBJECTIVE: Our objective was to study the hypothalamic volume in a cohort of patients with amyotrophic lateral sclerosis (ALS) including symptomatic and presymptomatic ALS mutation carriers. METHODS: High-resolution three-dimensional T1-weighted MRI datasets from 251 patients with sporadic ALS, 19 symptomatic and 32 presymptomatic ALS mutation carriers and 112 healthy controls (HC) were retrospectivally registered for manual delineation of the hypothalamus. The volume of the hypothalamus, in total or subdivided, was normalised to the intracranial volume and adjusted to age...
June 8, 2017: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/28579752/comparison-of-visual-acuity-refractive-outcomes-and-satisfaction-between-lasik-performed-with-a-microkeratome-and-a-femto-laser
#15
Sharif Hashmani, Nauman Hashmani, Hina Rajani, Priyanka Ramesh, Junaid Ahmed Soomro, Syed Rashid Hussain Shah, Jaish Kumar, Sayed Mustafa Mahmood Shah
PURPOSE: To compare refractive outcomes, visual acuities, and satisfaction of patients between those treated with laser-assisted in situ keratomileusis (LASIK) using a Hansatome microkeratome (HM) and femto-assisted laser (FAL). METHODS: This was a retrospective analysis of 1,366 eyes in 687 patients who underwent LASIK with an HM (n=1,137) and an FAL (n=229) at the two centers of Hashmanis Hospital, Karachi, Pakistan. Refractive outcomes, including sphere, cylinder, and spherical equivalent in diopters (D), and visual acuities were assessed both preoperatively and at 1 month follow-up...
2017: Clinical Ophthalmology
https://www.readbyqxmd.com/read/28558143/parsing-disease-relevant-protein-modifications-from-epiphenomena-perspective-on-the-structural-basis-of-sod1-mediated-als
#16
N D Schmitt, J N Agar
Conformational change and modification of proteins are involved in many cellular functions. However, they can also have adverse effects that are implicated in numerous diseases. How structural change promotes disease is generally not well-understood. This perspective illustrates how mass spectrometry (MS), followed by toxicological and epidemiological validation, can discover disease-relevant structural changes and therapeutic strategies. We (with our collaborators) set out to characterize the structural and toxic consequences of disease-associated mutations and post-translational modifications (PTMs) of the cytosolic antioxidant protein Cu/Zn-superoxide dismutase (SOD1)...
July 2017: Journal of Mass Spectrometry: JMS
https://www.readbyqxmd.com/read/28527045/amyotrophic-lateral-sclerosis-like-superoxide-dismutase-1-proteinopathy-is-associated-with-neuronal-loss-in-parkinson-s-disease-brain
#17
Benjamin G Trist, Katherine M Davies, Veronica Cottam, Sian Genoud, Richard Ortega, Stéphane Roudeau, Asuncion Carmona, Kasun De Silva, Valerie Wasinger, Simon J G Lewis, Perminder Sachdev, Bradley Smith, Claire Troakes, Caroline Vance, Christopher Shaw, Safa Al-Sarraj, Helen J Ball, Glenda M Halliday, Dominic J Hare, Kay L Double
Neuronal loss in numerous neurodegenerative disorders has been linked to protein aggregation and oxidative stress. Emerging data regarding overlapping proteinopathy in traditionally distinct neurodegenerative diseases suggest that disease-modifying treatments targeting these pathological features may exhibit efficacy across multiple disorders. Here, we describe proteinopathy distinct from classic synucleinopathy, predominantly comprised of the anti-oxidant enzyme superoxide dismutase-1 (SOD1), in the Parkinson's disease brain...
July 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28485128/alcoholysis-a-promising-technology-for-conversion-of-lignocellulose-and-platform-chemicals
#18
REVIEW
Shanhui Zhu, Jing Guo, Xun Wang, Jianguo Wang, Weibin Fan
In the catalytic conversion of lignocellulose to valuable products, the first entry point is to break down these biopolymers to sugar units or aromatic monomers, which is conventionally achieved by hydrolysis in water medium. Recent years have seen tremendous progress in the alcoholysis process, which has remarkable advantages, such as the avoidance of treating waste water, suppression of humins or chars, and enhancement of reaction rate and product yield. Advances have been focused on the alcoholysis of cellulose, hemicellulose, and lignin to alkyl glucosides, xylosides, and aromatic monomers, respectively...
June 22, 2017: ChemSusChem
https://www.readbyqxmd.com/read/28480639/pyrimethamine-significantly-lowers-cerebrospinal-fluid-cu-zn-superoxide-dismutase-in-amyotrophic-lateral-sclerosis-patients-with-sod1-mutations
#19
MULTICENTER STUDY
Dale J Lange, Mona Shahbazi, Vincenzo Silani, Albert C Ludolph, Jochen H Weishaupt, Senda Ajroud-Driss, Kara G Fields, Rahul Remanan, Stanley H Appel, Claudia Morelli, Alberto Doretti, Luca Maderna, Stefano Messina, Ulrike Weiland, Stefan L Marklund, Peter M Andersen
OBJECTIVE: Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose-dependent SOD1 reduction in cell culture systems. A previous phase 1 trial showed pyrimethamine lowers SOD1 levels in leukocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to familial amyotrophic lateral sclerosis (fALS/SOD1)...
June 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28472188/a-prion-like-mechanism-for-the-propagated-misfolding-of-sod1-from-in-silico-modeling-of-solvated-near-native-conformers
#20
Eamonn F Healy
A prion-like mechanism has been developed to explain the observed promotion of amyloid aggregation caused by conversion of structurally intact SOD1 to a misfolded form. Superoxide dismutase [Cu-Zn], or SOD1, is a homo-dimeric protein that functions as an antioxidant by scavenging for superoxide. The misfolding and aggregation of SOD1 is linked to inherited, or familial, amyotrophic lateral sclerosis (FALS), a progressive and fatal neurodegenerative disease. Aberrant SOD1 folding has also been strongly implicated in disease causation for sporadic ALS, or SALS, which accounts for ~90% of ALS cases...
2017: PloS One
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