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Myungjin Jo, Ah Young Chung, Nozomu Yachie, Minchul Seo, Hyejin Jeon, Youngpyo Nam, Yeojin Seo, Eunmi Kim, Quan Zhong, Marc Vidal, Hae Chul Park, Frederick P Roth, Kyoungho Suk
To understand disease mechanisms, a large-scale analysis of human-yeast genetic interactions was performed. Of 1305 human disease genes assayed, 20 genes exhibited strong toxicity in yeast. Human-yeast genetic interactions were identified by en masse transformation of the human disease genes into a pool of 4653 homozygous diploid yeast deletion mutants with unique barcode sequences, followed by multiplexed barcode sequencing to identify yeast toxicity modifiers. Subsequent network analyses focusing on amyotrophic lateral sclerosis (ALS)-associated genes, such as optineurin (OPTN) and angiogenin (ANG), showed that the human orthologs of the yeast toxicity modifiers of these ALS genes are enriched for several biological processes, such as cell death, lipid metabolism, and molecular transport...
September 2017: Genome Research
Jiahui Mao, Qin Xia, Chunfeng Liu, Zheng Ying, Hongfeng Wang, Guanghui Wang
Mutations in optineurin (OPTN) are associated with several human disorders including amyotrophic lateral sclerosis (ALS) and primary open-angle glaucoma (POAG). OPTN is known to be a multifunctional autophagy receptor that plays important roles in NF-κB signaling, vesicle trafficking, maintenance of the Golgi apparatus and autophagy. Given that a loss of neurons and an abnormal aggregation of disease proteins are two key features of neurodegenerative diseases, protein quality control systems are considered to be tightly associated with neurodegeneration...
May 15, 2017: Human Molecular Genetics
Ayumi Nishiyama, Tetsuya Niihori, Hitoshi Warita, Rumiko Izumi, Tetsuya Akiyama, Masaaki Kato, Naoki Suzuki, Yoko Aoki, Masashi Aoki
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of motor neurons. We have recently identified SOD1 and FUS mutations as the most common causes in a consecutive series of 111 familial ALS pedigrees in Japan. To reveal possible genetic causes for the remaining 51 patients with familial ALS (45 pedigrees), we performed targeted next-generation sequencing of 35 known ALS/motor neuron diseases-related genes. Known variants in ANG, OPTN, SETX, and TARDBP were identified in 6 patients...
May 2017: Neurobiology of Aging
James A Oakes, Maria C Davies, Mark O Collins
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder affecting motor neurons, resulting in progressive muscle weakness and death by respiratory failure. Protein and RNA aggregates are a hallmark of ALS pathology and are thought to contribute to ALS by impairing axonal transport. Mutations in several genes known to contribute to ALS result in deposition of their protein products as aggregates; these include TARDBP, C9ORF72, and SOD1. In motor neurons, this can disrupt transport of mitochondria to areas of metabolic need, resulting in damage to cells and can elicit a neuroinflammatory response leading to further neuronal damage...
February 2, 2017: Molecular Brain
E P McCann, K L Williams, J A Fifita, I S Tarr, J O'Connor, D B Rowe, G A Nicholson, I P Blair
Amyotrophic lateral sclerosis (ALS) is a clinically and genetically heterogeneous fatal neurodegenerative disease. Around 10% of ALS cases are hereditary. ALS gene discoveries have provided most of our understanding of disease pathogenesis. We aimed to describe the genetic landscape of ALS in Australia by assessing 1013 Australian ALS patients for known ALS mutations by direct sequencing, whole exome sequencing or repeat primed polymerase chain reaction. Age of disease onset and disease duration were used for genotype-phenotype correlations...
September 2017: Clinical Genetics
Yuriko Minegishi, Mao Nakayama, Daisuke Iejima, Kazuhide Kawase, Takeshi Iwata
Glaucoma is one of the leading causes of bilateral blindness, affecting nearly 57 million people worldwide. Glaucoma is characterized by a progressive loss of retinal ganglion cells and is often associated with intraocular pressure (IOP). Normal tension glaucoma (NTG), marked by normal IOP but progressive glaucoma, is incompletely understood. In 2002, Sarfarazi et al. identified FIP-2 gene mutations responsible for hereditary NTG, renaming this gene "optineurin" (OPTN). Further investigations by multiple groups worldwide showed that OPTN is involved in several critical cellular functions, such as NF-κB regulation, autophagy, and vesicle transport...
November 2016: Progress in Retinal and Eye Research
Seshiru Nakazawa, Daisuke Oikawa, Ryohei Ishii, Takashi Ayaki, Hirotaka Takahashi, Hiroyuki Takeda, Ryuichiro Ishitani, Kiyoko Kamei, Izumi Takeyoshi, Hideshi Kawakami, Kazuhiro Iwai, Izuho Hatada, Tatsuya Sawasaki, Hidefumi Ito, Osamu Nureki, Fuminori Tokunaga
Optineurin (OPTN) mutations cause neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and glaucoma. Although the ALS-associated E478G mutation in the UBAN domain of OPTN reportedly abolishes its NF-κB suppressive activity, the precise molecular basis in ALS pathogenesis still remains unclear. Here we report that the OPTN-UBAN domain is crucial for NF-κB suppression. Our crystal structure analysis reveals that OPTN-UBAN binds linear ubiquitin with homology to NEMO. TNF-α-mediated NF-κB activation is enhanced in OPTN-knockout cells, through increased ubiquitination and association of TNF receptor (TNFR) complex I components...
2016: Nature Communications
Jennifer A Fifita, Kelly L Williams, Vinod Sundaramoorthy, Emily P Mccann, Garth A Nicholson, Julie D Atkin, Ian P Blair
Mutations in the optineurin gene (OPTN) have been identified in a small proportion (<1%) of sporadic and familial ALS cases, and the exact role of optineurin in the pathogenesis of ALS remains unclear. To further examine the role of OPTN in ALS, we sought to identify novel ALS variants in OPTN and examine their potential for pathogenicity in vitro. Whole exome sequence data from 74 familial ALS cases were analysed for the presence of novel OPTN mutations. Pathogenicity was assessed by analysing effects on Golgi fragmentation, endoplasmic reticulum (ER) stress-linked CHOP activation, and cellular localization of optineurin in motor neuron-like NSC-34 cells expressing mutant optineurin...
August 18, 2016: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Yasushi Ito, Dimitry Ofengeim, Ayaz Najafov, Sudeshna Das, Shahram Saberi, Ying Li, Junichi Hitomi, Hong Zhu, Hongbo Chen, Lior Mayo, Jiefei Geng, Palak Amin, Judy Park DeWitt, Adnan Kasim Mookhtiar, Marcus Florez, Amanda Tomie Ouchida, Jian-bing Fan, Manolis Pasparakis, Michelle A Kelliher, John Ravits, Junying Yuan
Mutations in the optineurin (OPTN) gene have been implicated in both familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of this protein in the central nervous system (CNS) and how it may contribute to ALS pathology are unclear. Here, we found that optineurin actively suppressed receptor-interacting kinase 1 (RIPK1)-dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL)...
August 5, 2016: Science
Vincent Picher-Martel, Paul N Valdmanis, Peter V Gould, Jean-Pierre Julien, Nicolas Dupré
Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others...
July 11, 2016: Acta Neuropathologica Communications
Vijay Kumar, Asimul Islam, Md Imtaiyaz Hassan, Faizan Ahmad
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative disorders which are characterized by a rapid decline in cognitive and motor functions, and short survival. Both syndromes may be present within the same family or even in the same person. The genetic findings for both diseases also support the existence of a continuum, with mutations in the same genes being found in patients with ALS, FTD or FTD/ALS. Little is known about the molecular mechanisms underlying the differences in mutations of the same protein causing either ALS or FTD...
September 2016: Biochimica et Biophysica Acta
Andrew S Moore, Erika L F Holzbaur
Mitochondria play an essential role in maintaining cellular homeostasis. The removal of damaged or depolarized mitochondria occurs via mitophagy, in which damaged mitochondria are targeted for degradation via ubiquitination induced by PTEN-induced putative kinase 1 (PINK1) and Parkin. Mitophagy receptors, including optineurin (OPTN), nuclear dot 52 kDa protein (NDP52), and Tax1-binding protein 1 (TAX1BP1), are recruited to mitochondria via ubiquitin binding and mediate autophagic engulfment through their association with microtubule-associated protein light chain 3 (LC3)...
June 14, 2016: Proceedings of the National Academy of Sciences of the United States of America
Anna M Blokhuis, Max Koppers, Ewout J N Groen, Dianne M A van den Heuvel, Stefano Dini Modigliani, Jasper J Anink, Katsumi Fumoto, Femke van Diggelen, Anne Snelting, Peter Sodaar, Bert M Verheijen, Jeroen A A Demmers, Jan H Veldink, Eleonora Aronica, Irene Bozzoni, Jeroen den Hertog, Leonard H van den Berg, R Jeroen Pasterkamp
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment available. An increasing number of genetic causes of ALS are being identified, but how these genetic defects lead to motor neuron degeneration and to which extent they affect common cellular pathways remains incompletely understood. To address these questions, we performed an interactomic analysis to identify binding partners of wild-type (WT) and ALS-associated mutant versions of ATXN2, C9orf72, FUS, OPTN, TDP-43 and UBQLN2 in neuronal cells...
August 2016: Acta Neuropathologica
Min Zhu, Ang Li, Junyi Chen, Shenghai Zhang, Jihong Wu
Mutations in the optineurin gene (OPTN) have been found to be associated with glaucoma and amyotrophic lateral sclerosis (ALS). However, the mechanism by which this single gene mutation leads to neurodegeneration in those two diseases remains unrevealed. To study the roles of wild-type (WT) OPTN and its pathogenic mutants in neuronal survival, here we overexpressed SH-SY5Y cells with WT OPTN or its four mutants (E50K, M98K, Q398X and E478G), and detected their effects on neuronal viability under normal or oxidative stress conditions...
July 2016: Molecular and Cellular Neurosciences
Pei-Chien Tsai, Yi-Chien Liu, Kon-Ping Lin, Yo-Tsen Liu, Yi-Chu Liao, Cheng-Tsung Hsiao, Bing-Wen Soong, Ping-Keung Yip, Yi-Chung Lee
Mutations in the TBK1 gene were just recently identified to cause amyotrophic lateral sclerosis (ALS), and their role in ALS in various populations remains unclear. The aim of this study was to determine the frequency and spectrum of mutations in TBK1 in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of TBK1 were carried out by direct nucleotide sequencing in a cohort of 207 unrelated patients with ALS. Among them, the genetic diagnoses of 168 patients remained elusive after mutations in SOD1, C9ORF72, TARDBP, FUS, ATXN2, OPTN, VCP, UBQLN2, SQSTM1, PFN1, HNRNPA1, HNRNPA2B1, MATR3, CHCHD10, and TUBA4A had been excluded...
April 2016: Neurobiology of Aging
Li Di, Hai Chen, Yuwei Da, Suobing Wang, Xin-Ming Shen
Amyotrophic lateral sclerosis (ALS) is the most prevalent fatal motor neuron disease and ~10% of cases are hereditary. Mutations associated with ALS have been identified in more than 20 genes, but ALS type 8 (ALS8), which is caused by mutations in vesicle-associated membrane protein-associated protein B (VAPB), is rare. To date, the dominant missense mutation P56S, which is in the major sperm protein domain of VAPB, has been described in nine families of Portuguese-Brazilian origin and one family of German origin...
February 2016: Journal of Neurology
Chengyu Li, Ying Ji, Lu Tang, Nan Zhang, Ji He, Shan Ye, Xiaolu Liu, Dongsheng Fan
The purpose of this study was to assess the frequency of optineurin (OPTN) mutation in amyotrophic lateral sclerosis (ALS) patients from mainland China, as well as to characterize the relationship between OPTN mutation and clinical phenotypes. We examined the coding region of OPTN in 511 unrelated Chinese sporadic ALS (SALS) subjects and 204 healthy controls using a PCR direct sequencing strategy. Nine OPTN variants were identified, of which four were novel missense mutations: c.407C > T (p.A136V), c...
2015: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Joanna J Bury, J Robin Highley, Johnathan Cooper-Knock, Emily F Goodall, Adrian Higginbottom, Christopher J McDermott, Paul G Ince, Pamela J Shaw, Janine Kirby
Amyotrophic lateral sclerosis (ALS) is characterized by motor neurone loss resulting in muscle weakness, spasticity and ultimately death. 5-10% are caused by inherited mutations, most commonly C9ORF72, SOD1, TARDBP and FUS. Rarer genetic causes of ALS include mutation of optineurin (mt OPTN). Furthermore, optineurin protein has been localized to the ubiquitylated aggregates in several neurodegenerative diseases, including ALS. This study: (i) investigated the frequency of mt OPTN in ALS patients in England; (ii) characterized the clinical and neuropathological features of ALS associated with a mt OPTN; and (iii) investigated optineurin neuropathology in C9ORF72-related ALS (C9ORF72-ALS)...
April 2016: Neuropathology: Official Journal of the Japanese Society of Neuropathology
Emma Beeldman, Anneke J van der Kooi, Marianne de Visser, Merel C van Maarle, Fred van Ruissen, Frank Baas
Approximately 10% of motor neuron disease (MND) patients report a familial predisposition for MND. Autosomal recessively inherited MND is less common and is most often caused by mutations in the superoxide dismutase 1 (SOD1) gene. In 2010, autosomal recessively inherited mutations in the optineurin (OPTN) gene were found in 1% of Japanese patients with sporadic amyotrophic lateral sclerosis (ALS). Autosomal dominantly inherited OPTN mutations have been described as a cause of primary open-angle glaucoma in the Netherlands and were also found in two Dutch sporadic MND patients...
2015: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Keshav Thakur, Suresh Sharma, Sudesh Prabhakar, Pawan Gupta, Akshay Anand
BACKGROUND: Enzyme Linked Immunosorbent Assay (ELISA) is very sensitive assay which provides quantitative data about expression of antigens. However, its utility is based on certain parameters which vary in the experimental situations. PURPOSE: We aimed to analyse the dilution factor as an important parameter for determining the sensitivity of ELISA in human samples. METHODS: Total of n = 57 ALS patients and n = 48 normal controls were selected for the study...
January 2015: Annals of Neurosciences
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