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Michael Benatar, Joanne Wuu, Peter M Andersen, Vittoria Lombardi, Andrea Malaspina
OBJECTIVE: To evaluate neurofilament light (NfL) as a biomarker of the pre-symptomatic phase of amyotrophic lateral sclerosis (ALS). METHODS: The study population includes 84 individuals at risk for developing ALS, 34 controls, 17 ALS patients, and 10 phenoconverters (at-risk individuals observed both before and after the emergence of clinically manifest disease). At-risk individuals are enrolled through Pre-Symptomatic Familial ALS (Pre-fALS), a longitudinal natural history and biomarker study of individuals who are carriers of any ALS-associated gene mutation (in SOD1, C9orf72, TARDBP, FUS, VCP, etc...
July 16, 2018: Annals of Neurology
Danyang Tian, Jiao Li, Lu Tang, Nan Zhang, Dongsheng Fan
Previous research has identified CCNF mutations in familial (FALS) and sporadic amyotrophic lateral sclerosis (SALS), as well as in frontotemporal dementia (FTD). The aim of our study was to measure the frequency of CCNF mutations in a Chinese population. In total, 78 FALS patients, 581 SALS patients and 584 controls were included. We found 19 missense mutations, nine synonymous mutations and two intron variants. According to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines for the interpretation of sequence variants, eight variants were judged to be pathogenic or likely pathogenic variants...
2018: Frontiers in Aging Neuroscience
Viviana Greco, Alida Spalloni, Victor Corasolla Carregari, Luisa Pieroni, Silvia Persichilli, Nicola B Mercuri, Andrea Urbani, Patrizia Longone
Hydrogen sulfide (H₂S) is an endogenous gasotransmitter recognized as an essential body product with a dual, biphasic action. It can function as an antioxidant and a cytoprotective, but also as a poison with a high probability of causing brain damage when present at noxious levels. In a previous study, we measured toxic liquoral levels of H₂S in sporadic amyotrophic lateral sclerosis (ALS) patients and in the familial ALS (fALS) mouse model, SOD1G93A. In addition, we experimentally demonstrated that H₂S is extremely and selectively toxic to motor neurons, and that it is released by glial cells and increases Ca2+ concentration in motor neurons due to a lack of ATP...
July 10, 2018: Antioxidants (Basel, Switzerland)
Gye Sun Jeon, Yu-Mi Shim, Do-Yeon Lee, Jun-Soon Kim, MinJin Kang, So Hyun Ahn, Je-Young Shin, Dongho Geum, Yoon Ho Hong, Jung-Joon Sung
Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset, progressive neurodegenerative disorder with no known cure. Cu/Zn-superoxide dismutase (SOD1) was the first identified protein associated with familial ALS (fALS). Recently, TAR DNA-binding protein 43 (TDP-43) has been found to be a principal component of ubiquitinated cytoplasmic inclusions in neurons and glia in ALS. However, it remains unclear whether these ALS-linked proteins partly have a shared pathogenesis. Here, we determine the association between mutant SOD1 and the modification of TDP-43 and the relationship of pathologic TDP-43 to neuronal cytotoxicity in SOD1 ALS...
July 7, 2018: Molecular Neurobiology
Simona Damiano, Anna Sasso, Roberta Accetta, Marcellino Monda, Bruno De Luca, Luigi Michele Pavone, Anna Belfiore, Mariarosaria Santillo, Paolo Mondola
The constitutive secretion of antioxidant Cu-Zn Superoxide dismutase (SOD1) has been widely demonstrated in many cellular lines. In addition, we showed that as well as the basal SOD1 secretion, this enzyme is also exported through depolarization of excitable cells by high extracellular K concentration. Recent data showed that SOD1 was able to activate muscarinic M1 receptor producing the activation, via phospholipase C, of ERK1-2 and AKT pathways. It is also known that about 20% of familial amyotrophic lateral sclerosis (fALS) is due to mutations in the gene coding for SOD1...
2018: Frontiers in Physiology
Enrico Luchinat, Lucia Banci
Cellular structural biology methods are needed to characterize biological processes at atomic resolution in the physiological environment of the cell. Toward this goal, solution in-cell NMR is a powerful approach because it provides structural and dynamic data on macromolecules inside living cells. Several approaches have been developed for in-cell NMR in cultured human cells, which are needed to study processes related to human diseases that rely on the delivery of exogenous macromolecules to the cells. Such strategies, however, may not be applicable to proteins that are sensitive to the external environment or prone to aggregate and can introduce artifacts during protein purification or delivery...
June 19, 2018: Accounts of Chemical Research
Benjamin Guy Trist, Dominic James Hare, Kay Lorraine Double
Shared molecular pathologies between distinct neurodegenerative disorders offer unique opportunities to identify common mechanisms of neuron death, and apply lessons learned from one disease to another. Neurotoxic superoxide dismutase 1 (SOD1) proteinopathy in SOD1-associated familial amyotrophic lateral sclerosis (fALS) is recapitulated in idiopathic Parkinson disease (PD), suggesting that these two phenotypically distinct disorders share an etiological pathway, and tractable therapeutic target(s). Despite 25 years of research, the molecular determinants underlying SOD1 misfolding and toxicity in fALS remain poorly understood...
May 16, 2018: Cell Chemical Biology
Marta Gromicho, Susana Pinto, Eugeniu Gisca, Ana Catarina Pronto-Laborinho, Mamede de Carvalho
Mutation frequency of the 2 main amyotrophic lateral sclerosis (ALS)-related genes, C9orf72 and SOD1, varies considerably across the world. We analyzed those genes in a large population of Portuguese ALS patients (n = 371) and recorded demographic and clinical features. Familial ALS (FALS) was disclosed in 11.6% of patients. Mutations in either SOD1 or C9orf72 were found in 9.2% of patients and accounted for 40% of FALS and 5.2% of sporadic ALS. SOD1 mutations were rare (0.83%), but a novel and probably disease-causing mutation was identified: p...
May 14, 2018: Neurobiology of Aging
David Gonzalez, Daniela L Rebolledo, Lina M Correa, Felipe Court, Waldo Cerpa, Kenneth E Lipson, Brigitte van Zundert, Enrique Brandan
Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset progressive neurodegenerative disease characterized by upper and lower motoneuron degeneration. 20% of familial ALS (fALS) cases are explained by mutations in the superoxide dismutase 1 (SOD1) enzyme. Although more than twenty years have passed since the generation of the first ALS mouse model, the precise molecular mechanisms of ALS pathogenesis remain unknown. CTGF/CCN2 is a matricellular protein with associated fibrotic activity that is up-regulated in several chronic diseases...
May 30, 2018: Human Molecular Genetics
Marie Ryan, Mark Heverin, Mark A Doherty, Nicola Davis, Emma M Corr, Alice Vajda, Niall Pender, Russell McLaughlin, Orla Hardiman
Objective: To assess temporal trends in familial amyotrophic lateral sclerosis (FALS) incidence rates in an Irish population and to determine factors influencing FALS ascertainment. Methods: Population-based data collected over 23 years, using the Irish amyotrophic lateral sclerosis (ALS) register and DNA biobank, were analyzed and age-standardized rates of FALS and associated familial neuropsychiatric endophenotypes were identified. Results: Between 1994 and 2016, 269 patients with a family history of ALS from 197 unique families were included on the register...
June 2018: Neurology. Genetics
Kang Zhang, Qing Liu, Keqiang Liu, Dongchao Shen, Hongfei Tai, Shi Shu, Qingyun Ding, Hanhui Fu, Shuangwu Liu, Zhili Wang, Xiaoguang Li, Mingsheng Liu, Xue Zhang, Liying Cui
Objective: To investigate the genetic contribution of ANXA11 , a gene associated with amyotrophic lateral sclerosis (ALS), in Chinese ALS patients with and without cognitive dementia. Methods: Sequencing all the coding exons of ANXA11 and intron-exon boundaries in 18 familial amyotrophic lateral sclerosis (FALS), 353 unrelated sporadic amyotrophic lateral sclerosis (SALS), and 12 Chinese patients with ALS-frontotemporal lobar dementia (ALS-FTD). The transcripts in peripheral blood generated from a splicing mutation were examined by reverse transcriptase PCR...
June 2018: Neurology. Genetics
Simona Portaro, Teresa Brizzi, Antonino Naro, Valeria Conti Nibali, Rosa Morabito, Alessia Bramanti, Rocco Salvatore Calabrò
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting upper and lower motor neurones. It can be either familial (fALS) or sporadic (sALS). ALS is characterized by muscle weakness and atrophy that can involve the limbs and trunk (i.e. the spinal form of the disease) or speech and swallowing (i.e. the bulbar form). The aetiology of sALS remains unclear although a gene-environment interaction has been proposed as a concomitant trigger for the neurodegenerative process together with viral infections, smoking, heavy metals and pesticide exposure...
January 1, 2018: Journal of International Medical Research
Yoshifumi Sonobe, Ghanashyam Ghadge, Katsuhisa Masaki, Ataman Sendoel, Elaine Fuchs, Raymond P Roos
Expansion of a hexanucleotide repeat (HRE), GGGGCC, in the C9ORF72 gene is recognized as the most common cause of familial amyotrophic lateral sclerosis (FALS), frontotemporal dementia (FTD) and ALS-FTD, as well as 5-10% of sporadic ALS. Despite the location of the HRE in the non-coding region (with respect to the main C9ORF72 gene product), dipeptide repeat proteins (DPRs) that are thought to be toxic are translated from the HRE in all three reading frames from both the sense and antisense transcript. Here, we identified a CUG that has a good Kozak consensus sequence as the translation initiation codon...
August 2018: Neurobiology of Disease
Nazrat Mirza, Thao-Ly Phan, June Tester, Angela Fals, Cristina Fernandez, George Datto, Elizabeth Estrada, Ihuoma Eneli
Severe obesity defined as an age- and gender-specific body mass index ≥120% of the 95th percentile in children younger than 5 years is well recognized as a significant challenge for prevention and treatment. This article provides an overview of the prevalence, classification of obesity severity, patterns of weight gain trajectory, medical and genetic risk factors, and comorbid disorders among young children with an emphasis on severe obesity. Studies suggest rapid weight gain trajectory in infancy, maternal smoking, maternal gestational diabetes, and genetic conditions are associated with an increased risk for severe obesity in early childhood...
May 23, 2018: Childhood Obesity
Edoardo Del Poggetto, Angelo Toto, Chiara Aloise, Francesco Di Piro, Ludovica Gori, Francesco Malatesta, Stefano Gianni, Fabrizio Chiti, Francesco Bemporad
A set of missense mutations in the gene encoding profilin-1 has been linked to the onset of familial forms of ALS (fALS), also known as Lou Gehrig's disease. The pathogenic potential of these mutations is linked to the formation of intracellular inclusions of the mutant proteins and correlates with the mutation-induced destabilization of its native, fully folded state. However, the mechanism by which these mutations promote misfolding and self-assembly is yet unclear. Here, using temperature-jump and stopped-flow kinetic measurements, we show that, during refolding, WT profilin-1 transiently populates a partially folded (PF) state endowed with hydrophobic clusters exposed to the solvent and with no detectable secondary structure...
June 29, 2018: Journal of Biological Chemistry
Shuran He, Yongtao Li, Liping Weng, Jinjin Wang, Jinxian He, Yonglin Liu, Kun Zhang, Qihong Wu, Yulong Zhang, Zhen Zhang
In present study, the feasibility of applying a natural adsorbent with Fe3+ modification (Fe3+ -modified argillaceous limestone, FAL) on the competitive adsorption of heavy metals (i.e., Cd2+ , Pb2+ and Ni2+ ) was evaluated. The current results revealed an efficient adsorption on Cd2+ , Pb2+ and Ni2+ in mono-metal system. Further experiments demonstrated a high selectivity of Pb2+ during the competitive adsorption of Cd2+ , Pb2+ and Ni2+ . The adsorption selectivity of the metal ions followed the order of Pb ≫ Cd > Ni...
October 1, 2018: Science of the Total Environment
Y-H Taguchi, Hsiuying Wang
Amyotrophic lateral sclerosis (ALS) is among the severe neuro degenerative diseases that lack widely available effective treatments. As the disease progresses, patients lose the control of voluntary muscles. Although the neuronal degeneration is the cause of this disease, the failure mechanism is still unknown. In order to seek genetic mechanisms that initiate and progress ALS, the association of microRNA (miRNA) expression with this disease was considered. Serum miRNAs from healthy controls, sporadic ALS (sALS), familial ALS (fALS) and ALS mutation carriers were investigated...
April 28, 2018: International Journal of Molecular Sciences
J F Kögel, D A Sorokin, A Khvorost, M Scott, K Harms, D Himmel, I Krossing, J Sundermeyer
Herein we present the synthesis of the two Lewis acids Al[N(C6 F5 )2 ]3 (ALTA) and Ga[N(C6 F5 )2 ]3 (GATA) via salt elimination reactions. The metal complexes were characterized by NMR-spectroscopic methods and X-ray diffraction analysis revealing the stabilization of the highly Lewis acidic metal centers by secondary metal-fluorine contacts. The Lewis acidic properties of Al[N(C6 F5 )2 ]3 and Ga[N(C6 F5 )2 ]3 are demonstrated by reactions with Lewis bases resulting in the formation of metallates accompanied by crucial structural changes...
January 7, 2018: Chemical Science
Jacob J Riehm, Lijun Wang, Ghanashyam Ghadge, Michael Teng, Ana M Correa, Jeremy D Marks, Raymond P Roos, Michael J Allen
Here we report a gain in function for mutant (mt) superoxide dismutase I (SOD1), a cause of familial amyotrophic lateral sclerosis (FALS), wherein small soluble oligomers of mtSOD1 acquire a membrane toxicity. Phosphatidylglycerol (PG) lipid domains are selectively targeted, which could result in membrane damage or "toxic channels" becoming active in the bilayer. This PG-selective SOD1-mediated membrane toxicity is largely reversible in vitro by a widely-available FDA-approved surfactant and membrane-stabilizer P188...
July 2018: Neurobiology of Disease
Yanran Li, Bo Sun, Siyu Chen, Yuting Ren, Fang Cui, Fei Yang, Zhaohui Chen, Li Ling, Xusheng Huang
We reported a novel heterozygous duplication mutation (c.272_274dupACA, D90_K91insN) in exon 4 of the SOD1 gene in a Chinese pedigree. This pedigree demonstrates an autosomal dominant pattern of inheritance, with potentially reduced penetrance. The clinical phenotype was rather uniform with a distal lower extremity onset, predominant involvement of lower motor neurons (LMNs), and a relatively short survival time (mean 2.6 years) compared with other mutations in the loop V structure of SOD1. We also detected that the average SOD1 activity in D90_K91insN mutation carriers is 68...
April 2, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
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