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https://www.readbyqxmd.com/read/27693724/significance-of-optineurin-mutations-in-glaucoma-and-other-diseases
#1
REVIEW
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
https://www.readbyqxmd.com/read/27552911/linear-ubiquitination-is-involved-in-the-pathogenesis-of-optineurin-associated-amyotrophic-lateral-sclerosis
#2
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
https://www.readbyqxmd.com/read/27534431/a-novel-amyotrophic-lateral-sclerosis-mutation-in-optn-induces-er-stress-and-golgi-fragmentation-in-vitro
#3
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
https://www.readbyqxmd.com/read/27493188/ripk1-mediates-axonal-degeneration-by-promoting-inflammation-and-necroptosis-in-als
#4
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
https://www.readbyqxmd.com/read/27400686/from-animal-models-to-human-disease-a-genetic-approach-for-personalized-medicine-in-als
#5
REVIEW
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
https://www.readbyqxmd.com/read/27318084/delineating-the-relationship-between-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia-sequence-and-structure-based-predictions
#6
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
https://www.readbyqxmd.com/read/27247382/dynamic-recruitment-and-activation-of-als-associated-tbk1-with-its-target-optineurin-are-required-for-efficient-mitophagy
#7
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
https://www.readbyqxmd.com/read/27164932/comparative-interactomics-analysis-of-different-als-associated-proteins-identifies-converging-molecular-pathways
#8
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
https://www.readbyqxmd.com/read/26956627/effects-of-optineurin-mutants-on-sh-sy5y-cell-survival
#9
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
https://www.readbyqxmd.com/read/26804609/mutational-analysis-of-tbk1-in-taiwanese-patients-with-amyotrophic-lateral-sclerosis
#10
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
https://www.readbyqxmd.com/read/26566915/atypical-familial-amyotrophic-lateral-sclerosis-with-initial-symptoms-of-pain-or-tremor-in-a-chinese-family-harboring-vapb-p56s-mutation
#11
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
https://www.readbyqxmd.com/read/26503823/optineurin-mutations-in-patients-with-sporadic-amyotrophic-lateral-sclerosis-in-china
#12
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
https://www.readbyqxmd.com/read/26303227/oligogenic-inheritance-of-optineurin-optn-and-c9orf72-mutations-in-als-highlights-localisation-of-optn-in-the-tdp-43-negative-inclusions-of-c9orf72-als
#13
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
https://www.readbyqxmd.com/read/26203661/a-dutch-family-with-autosomal-recessively-inherited-lower-motor-neuron-predominant-motor-neuron-disease-due-to-optineurin-mutations
#14
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
https://www.readbyqxmd.com/read/26124549/revisiting-the-dilution-factor-as-vital-parameter-for-sensitivity-of-elisa-assay-in-csf-and-plasma
#15
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
https://www.readbyqxmd.com/read/25943890/whole-genome-sequencing-reveals-important-role-for-tbk1-and-optn-mutations-in-frontotemporal-lobar-degeneration-without-motor-neuron-disease
#16
Cyril Pottier, Kevin F Bieniek, NiCole Finch, Maartje van de Vorst, Matt Baker, Ralph Perkersen, Patricia Brown, Thomas Ravenscroft, Marka van Blitterswijk, Alexandra M Nicholson, Michael DeTure, David S Knopman, Keith A Josephs, Joseph E Parisi, Ronald C Petersen, Kevin B Boylan, Bradley F Boeve, Neill R Graff-Radford, Joris A Veltman, Christian Gilissen, Melissa E Murray, Dennis W Dickson, Rosa Rademakers
Frontotemporal lobar degeneration with TAR DNA-binding protein 43 inclusions (FTLD-TDP) is the most common pathology associated with frontotemporal dementia (FTD). Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) and mutations in progranulin (GRN) are the major known genetic causes of FTLD-TDP; however, the genetic etiology in the majority of FTLD-TDP remains unexplained. In this study, we performed whole-genome sequencing in 104 pathologically confirmed FTLD-TDP patients from the Mayo Clinic brain bank negative for C9ORF72 and GRN mutations and report on the contribution of rare single nucleotide and copy number variants in 21 known neurodegenerative disease genes...
July 2015: Acta Neuropathologica
https://www.readbyqxmd.com/read/25855473/functional-analysis-of-optineurin-and-some-of-its-disease-associated-mutants
#17
REVIEW
Megha Bansal, Ghanshyam Swarup, Dorairajan Balasubramanian
Optineurin is a multifunctional protein involved in a variety of cellular functions such as protein trafficking by vesicles, autophagy, and signal transduction. Certain mutations in optineurin (gene OPTN) are associated with neurodegenerative diseases like glaucoma and amyotrophic lateral sclerosis (ALS). Optineurin is also seen in pathological structures present in several other neurodegenerative diseases. In glaucoma, loss of vision occurs due to progressive degeneration of retinal ganglion cells, and perhaps loss of photoreceptor cone cells as well...
February 2015: IUBMB Life
https://www.readbyqxmd.com/read/25801386/temporal-dynamics-of-park2-parkin-and-optn-optineurin-recruitment-during-the-mitophagy-of-damaged-mitochondria
#18
Yvette C Wong, Erika L F Holzbaur
Damaged mitochondria are selectively degraded via autophagy in a regulated pathway known as mitophagy. Parkinson disease-linked proteins PINK1 (PTEN induced putative kinase 1) and PARK2 (parkin RBR E3 ubiquitin protein ligase) are recruited to the outer mitochondrial membrane upon mitochondrial damage, leading to the PARK2-mediated ubiquitination of mitochondrial proteins. Here, we discuss our recent work demonstrating that OPTN (optineurin) is recruited to damaged mitochondria, serving as an autophagy receptor for autophagosome formation around mitochondria...
2015: Autophagy
https://www.readbyqxmd.com/read/25771394/mutational-analysis-of-matr3-in-taiwanese-patients-with-amyotrophic-lateral-sclerosis
#19
Kon-Ping Lin, Pei-Chien Tsai, Yi-Chu Liao, Wei-Ting Chen, Ching-Piao Tsai, Bing-Wen Soong, Yi-Chung Lee
Mutations in the MATR3 gene were just recently identified to cause familial amyotrophic lateral sclerosis, and their role in amyotrophic lateral sclerosis (ALS) in various populations remains unclear. The aim of this study was to determine the frequency and spectrum of mutations in MATR3 in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of MATR3 were carried out by direct nucleotide sequencing in a cohort of 207 unrelated patients with ALS. Among them, the genetic diagnoses of 169 patients remained elusive after mutations in SOD1, C9ORF72, TARDBP, FUS, ATXN2, OPTN, VCP, UBQLN2, SQSTM1, PFN1, HNRNPA1, and HNRNPA2B1 had been excluded...
May 2015: Neurobiology of Aging
https://www.readbyqxmd.com/read/25700176/exome-sequencing-in-amyotrophic-lateral-sclerosis-identifies-risk-genes-and-pathways
#20
Elizabeth T Cirulli, Brittany N Lasseigne, Slavé Petrovski, Peter C Sapp, Patrick A Dion, Claire S Leblond, Julien Couthouis, Yi-Fan Lu, Quanli Wang, Brian J Krueger, Zhong Ren, Jonathan Keebler, Yujun Han, Shawn E Levy, Braden E Boone, Jack R Wimbish, Lindsay L Waite, Angela L Jones, John P Carulli, Aaron G Day-Williams, John F Staropoli, Winnie W Xin, Alessandra Chesi, Alya R Raphael, Diane McKenna-Yasek, Janet Cady, J M B Vianney de Jong, Kevin P Kenna, Bradley N Smith, Simon Topp, Jack Miller, Athina Gkazi, Ammar Al-Chalabi, Leonard H van den Berg, Jan Veldink, Vincenzo Silani, Nicola Ticozzi, Christopher E Shaw, Robert H Baloh, Stanley Appel, Ericka Simpson, Clotilde Lagier-Tourenne, Stefan M Pulst, Summer Gibson, John Q Trojanowski, Lauren Elman, Leo McCluskey, Murray Grossman, Neil A Shneider, Wendy K Chung, John M Ravits, Jonathan D Glass, Katherine B Sims, Vivianna M Van Deerlin, Tom Maniatis, Sebastian D Hayes, Alban Ordureau, Sharan Swarup, John Landers, Frank Baas, Andrew S Allen, Richard S Bedlack, J Wade Harper, Aaron D Gitler, Guy A Rouleau, Robert Brown, Matthew B Harms, Gregory M Cooper, Tim Harris, Richard M Myers, David B Goldstein
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS...
March 27, 2015: Science
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