Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis.

doi:10.1016/J.FREERADBIOMED.2013.06.029

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Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis.

Journal Article•DOI•

Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis.

Emanuele D'Amico¹, Pam Factor-Litvak², Regina M. Santella², Hiroshi Mitsumoto¹•Institutions (2)

Columbia University Medical Center¹, Columbia University²

01 Dec 2013-Free Radical Biology and Medicine (NIH Public Access)-Vol. 65, pp 509-527

TL;DR: Investigation indicates that agricultural chemicals, heavy metals, military service, professional sports, excessive physical exertion, chronic head trauma, and certain foods might be modestly associated with ALS risk, with a stronger association between risk and smoking.

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About: This article is published in Free Radical Biology and Medicine.The article was published on 2013-12-01 and is currently open access. It has received 264 citations till now. The article focuses on the topics: Oxidative stress & Amyotrophic lateral sclerosis.

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Journal Article•DOI•

Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial

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Koji Abe, Masashi Aoki, Shoji Tsuji, Yasuto Itoyama, Gen Sobue, Masanori Togo, Chikuma Hamada, Masahiko Tanaka, Makoto Akimoto, Kazue Nakamura, Fumihiro Takahashi, Kazuoki Kondo, Hiide Yoshino, Hidenao Sasaki, Ichiro Yabe, Shizuki Doi, Hitoshi Warita, Takashi Imai, Hiroaki Ito, Mitsumasa Fukuchi, Etsuko Osumi, Manabu Wada, Imaharu Nakano, Mitsuya Morita, Katsuhisa Ogata, Yuichi Maruki, Kimiko Ito, Osamu Kano, Mineo Yamazaki, Yuji Takahashi, Hiroyuki Ishiura, Mieko Ogino, Ryoko Koike, Chiho Ishida, Tsuyoshi Uchiyama, Kouichi Mizoguchi, Tomokazu Obi, Hirohisa Watanabe, Naoki Atsuta, Ikuko Aiba, Akira Taniguchi, Hideyuki Sawada, Takanori Hazama, Harutoshi Fujimura, Hirofumi Kusaka, Takenobu Kunieda, Hitoshi Kikuchi, Hidenori Matsuo, Hidetsugu Ueyama, Kazutoshi Uekawa, Masaki Ueda, Aiko Murakami, Rie Sumii, Takuya Kudou, Kazunori Morimoto, Takatomo Yoneoka, Manabu Hirai, Kouichi Sasaki, Hidetomo Terai, Tomoko Natori, Hiroshi Matsui, Kuniko Kotani, Kaori Yoshida, Tomohisa Iwasaki - Show less +60 more

01 Jul 2017-Lancet Neurology

TL;DR: The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation and the least-squares mean difference between groups was 2·49 (SE 0·76, 95% CI 0·99-3·98) in favour of edaravone.

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Abstract: Summary Background In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating Scale (ALSFRS-R) score compared with placebo Post-hoc analysis of these data revealed that patients in an early stage with definite or probable diagnosis of ALS, defined by the revised El Escorial criteria, who met a select set of inclusion criteria showed a greater magnitude of effect than did the full study population We aimed to substantiate this post-hoc result and assess safety and efficacy of edaravone in a phase 3 trial that focused on patients with early stage ALS who met the post-hoc analysis inclusion criteria Methods In this phase 3, randomised, double-blind, parallel-group study, patients aged 20–75 years with ALS of grade 1 or 2 in the Japan ALS Severity Classification, scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, definite or probable ALS according to the revised El Escorial criteria, and disease duration of 2 years or less were recruited from 31 hospitals in Japan Eligible patients also had a decrease of 1–4 points in the ALSFRS-R score during a 12-week observation period before randomisation Patients meeting all criteria were then randomly assigned 1:1 to receive 60 mg intravenous edaravone or intravenous saline placebo for 6 cycles (4 weeks per cycle with 2 weeks on, 2 weeks off) for a total treatment duration of 24 weeks In cycle 1, the study drug or placebo was administered once per day for 14 days within a 14 day period, followed by the drug-free period In cycle 2 and thereafter, the study drug or placebo was administered for 10 days within a 14 day period, followed by a 2 week drug-free period Participants and investigators, including those assessing outcomes, were masked to treatment allocation The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation The primary outcome was assessed in all patients who had received at least one treatment infusion, had at least one assessment post-baseline, and reached the end of cycle 3 For patients with missing values at the end of cycle 6, data were imputed by the last observation carried forward (LOCF) method, provided the patients had completed at least cycle 3 Safety was assessed in all patients who had received at least one treatment infusion and had at least one assessment post-baseline This trial is registered with ClinicalTrialsgov, NCT01492686 Findings Between Nov 28, 2011, and Sept 3, 2014, we screened 213 patients, and enrolled 192 as potential participants Of these, 137 patients completed the observation period: 69 were randomly assigned to receive edaravone, and 68 were randomly assigned to receive placebo 68 patients taking edaravone and 66 taking placebo were included in the primary efficacy analysis For the primary outcome, the change in ALSFRS-R score was −5·01 (SE 0·64) in the edavarone group and −7·50 (0·66) in the placebo group The least-squares mean difference between groups was 2·49 (SE 0·76, 95% CI 0·99–3·98; p=0·0013) in favour of edaravone Treatment-emergent adverse events were reported in 58 (84%) patients receiving edaravone and 57 (84%) patients receiving placebo 11 (16%) patients taking edaravone and 16 (24%) taking placebo had serious adverse events, and one (1%) patient receiving edaravone and four (6%) patients receiving placebo had adverse events (one dysphagia in edaravone group and one dyspnoea, two respiratory disorder, and one rash in the placebo group) that led to withdrawal Interpretation Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria Funding Mitsubishi Tanabe Pharma Corporation

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593 citations

Journal Article•DOI•

Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications.

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Zewen Liu¹, Tingyang Zhou², Tingyang Zhou¹, Alexander C. Ziegler³, Peter Dimitrion³, Li Zuo², Li Zuo¹ - Show less +3 more•Institutions (3)

The Ohio State University Wexner Medical Center¹, Ohio State University², Johns Hopkins University³

12 Jul 2017-Oxidative Medicine and Cellular Longevity

TL;DR: Novel antioxidants have shown great potential in mediating disease phenotypes and could be an area of interest for further research, as well as a highlight on the antioxidant-based therapies for alleviating disease severity.

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Abstract: Increasing numbers of individuals, particularly the elderly, suffer from neurodegenerative disorders. These diseases are normally characterized by progressive loss of neuron cells and compromised motor or cognitive function. Previous studies have proposed that the overproduction of reactive oxygen species (ROS) may have complex roles in promoting the disease development. Research has shown that neuron cells are particularly vulnerable to oxidative damage due to their high polyunsaturated fatty acid content in membranes, high oxygen consumption, and weak antioxidant defense. However, the exact molecular pathogenesis of neurodegeneration related to the disturbance of redox balance remains unclear. Novel antioxidants have shown great potential in mediating disease phenotypes and could be an area of interest for further research. In this review, we provide an updated discussion on the roles of ROS in the pathological mechanisms of Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia, as well as a highlight on the antioxidant-based therapies for alleviating disease severity.

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552 citations

Cites background from "Clinical perspective on oxidative s..."

...to lead to mitochondrial dysfunction contributing to the pathogenesis of sALS [118]....
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Journal Article•DOI•

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential.

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Na Xie¹, Lu Zhang, Wei Gao¹, Canhua Huang², Canhua Huang¹, Peter E. Huber³, Xiaobo Zhou⁴, Changlong Li¹, Guobo Shen, Bingwen Zou³, Bingwen Zou¹ - Show less +7 more•Institutions (4)

Sichuan University¹, Chengdu University of Traditional Chinese Medicine², German Cancer Research Center³, Heidelberg University⁴

07 Oct 2020-Signal Transduction and Targeted Therapy

TL;DR: Recent advances in the understanding of the molecular mechanisms of NAD -regulated physiological responses to stresses, the contribution of NAD + deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention are summarized.

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Abstract: Nicotinamide adenine dinucleotide (NAD+) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD+ on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD+-dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP+. Prolonged disequilibrium of NAD+ metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD+-regulated physiological responses to stresses, the contribution of NAD+ deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.

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282 citations

Journal Article•DOI•

The isoprostanes--25 years later.

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Ginger L. Milne¹, Qi Dai¹, L. Jackson Roberts¹•Institutions (1)

Vanderbilt University¹

01 Apr 2015-Biochimica et Biophysica Acta

TL;DR: Special focus is given to the use of IsoPs as biomarkers in obesity, ischemia-reperfusion injury, the central nervous system, cancer, and genetic disorders, and attention is paid to diet and lifestyle factors that can affect endogenous levels of ISoPs.

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266 citations

Cites background from "Clinical perspective on oxidative s..."

...To that end, F2-IsoPs have been shown to increase in a number of chronic neurodegenerative diseases including Alzheimer’s disease (AD) [138–141], Huntington’s disease [142], Parkinson’s disease [143,144], and amyotrophic lateral sclerosis (ALS) [145]....
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Journal Article•DOI•

Implications of glial nitric oxide in neurodegenerative diseases.

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Jose Enrique Yuste¹, Ernesto Tarragon², Carmen María Campuzano¹, Francisco Ros-Bernal¹•Institutions (2)

James I University¹, University of Liège²

17 Aug 2015-Frontiers in Cellular Neuroscience

TL;DR: Information is provided about the role of NO, glial activation and age-related processes in the central nervous system (CNS) that may be helpful in the isolation of new therapeutic targets for aging and neurodegenerative diseases.

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Abstract: Nitric oxide (NO) is a pleiotropic janus-faced molecule synthesized by nitric oxide synthases (NOS) which plays a critical role in a number of physiological and pathological processes in humans. The physiological roles of NO depend on its local concentrations, as well as its availability and the nature of downstream target molecules. Its double-edged sword action has been linked to neurodegenerative disorders. Excessive NO production, as the evoked by inflammatory signals, has been identified as one of the major causative reasons for the pathogenesis of several neurodegenerative diseases. Moreover, excessive NO synthesis under neuroinflammation leads to the formation of reactive nitrogen species and neuronal cell death. There is an intimate relation between microglial activation, NO and neuroinflammation in the human brain. The role of NO in neuroinflammation has been defined in animal models where this neurotransmitter can modulate the inflammatory process acting on key regulatory pathways, such as those associated with excitotoxicity processes induced by glutamate accumulation and microglial activation. Activated glia express inducible NOS and produce NO that triggers calcium mobilization from the endoplasmic reticulum, activating the release of vesicular glutamate from astroglial cells resulting in neuronal death. This change in microglia potentially contributes to the increased age-associated susceptibility and neurodegeneration. In the current review, information is provided about the role of NO, glial activation and age-related processes in the central nervous system (CNS) that may be helpful in the isolation of new therapeutic targets for aging and neurodegenerative diseases.

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254 citations

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Journal Article•DOI•

Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis

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Daniel R. Rosen¹•Institutions (1)

Harvard University¹

04 Mar 1993-Nature

TL;DR: Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.

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Abstract: Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord. Its cause is unknown and it is uniformly fatal, typically within five years. About 10% of cases are inherited as an autosomal dominant trait, with high penetrance after the sixth decade. In most instances, sporadic and autosomal dominant familial ALS (FALS) are clinically similar. We have previously shown that in some but not all FALS pedigrees the disease is linked to a genetic defect on chromosome 21q (refs 8, 9). Here we report tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O2.- to O2 and H2O2 (ref. 10). Given this linkage and the potential role of free radical toxicity in other neurodenegerative disorders, we investigated SOD1 as a candidate gene in FALS. We identified 11 different SOD1 missense mutations in 13 different FALS families.

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6,733 citations

"Clinical perspective on oxidative s..." refers background in this paper

...TDP-43 inclusions are now known to be present in the majority of ALS cases, including ALS-FTD, sALS, non-SOD1 fALS, and the ALS-Parkinson disease (PD) complex in Guam [178–181]....
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...They account for approximately 15–20% of fALS cases, and thus SOD1 mutations are the second most frequent known cause of fALS after C9ORF72 [8,9,225]....
[...]
...SOD1 SOD1, or Cu/Zn-SOD, was the first identified and more comprehensively studied antioxidant enzyme of the SOD family; mitochondrial Mn-SOD (SOD2) and extracellular Cu/Zn-SOD (SOD3) also exist [for review see 25,223]....
[...]
...The mechanisms underlying how wild-type SOD1 is misfolded in these ALS cases remain to be clarified [229,235]....
[...]
...[180] Maekawa, S; Leigh, PN; King, A; Jones, E; Steele, JC; Bodi, I; Shaw, CE; Hortobagyi, T; Al-Sarraj, S. TDP-43 is consistently co-localized with ubiquitinated inclusions in sporadic and Guam amyotrophic lateral sclerosis but not in familial amyotrophic lateral sclerosis with and without SOD1 mutations....
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Journal Article•DOI•

Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

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Manuela Neumann¹, Deepak M. Sampathu¹, Linda K. Kwong¹, Adam C. Truax¹, Matthew Micsenyi¹, Thomas T. Chou¹, Jennifer Bruce¹, Theresa Schuck¹, Murray Grossman¹, Christopher M. Clark¹, Leo McCluskey¹, Bruce L. Miller², Eliezer Masliah³, Ian R. A. Mackenzie⁴, Howard Feldman⁴, Wolfgang Feiden, Hans A. Kretzschmar⁵, John Q. Trojanowski¹, Virginia M.-Y. Lee¹ - Show less +15 more•Institutions (5)

University of Pennsylvania¹, University of California, San Francisco², University of California, San Diego³, University of British Columbia⁴, Ludwig Maximilian University of Munich⁵

06 Oct 2006-Science

TL;DR: It is shown that TDP-43 is the major disease protein in both frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis.

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Abstract: Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.

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5,440 citations

"Clinical perspective on oxidative s..." refers background in this paper

...TDP-43 inclusions are now known to be present in the majority of ALS cases, including ALS-FTD, sALS, non-SOD1 fALS, and the ALS-Parkinson disease (PD) complex in Guam [178–181]....
[...]
...[181] Murray, ME; DeJesus-Hernandez, M; Rutherford, NJ; Baker, M; Duara, R; Graff-Radford, NR; Wszolek, ZK; Ferman, TJ; Josephs, KA; Boylan, KB; Rademakers, R; Dickson, DW. Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72....
[...]
...The importance of TDP-43 in ALS quickly became evident when researchers discovered TDP-43 inclusions in ALS and frontotemporal dementia (FTD) [176,177]....
[...]
...A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD....
[...]
...8 82 83 84 85 86 87 88 89 90 91ll rights reserved. ase; ALS, amyotrophic lateral sclerosis; fALS, familial ALS; sALS, sporadic ALS; ANG, angiogenin; ApoE, apolipoprotein E; CTE, chronic traumatic encephalopathy; ER, endoplasmic reticulum; FVC, forced vital capacity; IsoP, isoprostane; FTD, h-density lipoprotein; HNE, 4-hydroxy-2-nonenal; LDL, low-density lipoprotein; MDA, malondialdehyde; MND, motor e synthetase; 8-oxodG, 8-oxo-deoxyguanosine; OXR1, oxidation resistance 1; PD, Parkinson disease; PON, paraoxonase n species; SMN, survival motor neuron; SNP, single-nucleotide polymorphism; SOD1, superoxide dismutase 1; TBARS, DNA-binding protein; VEGF, vascular endothelial growth factor. oto). l. Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis....
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Journal Article•DOI•

Oxidative stress: oxidants and antioxidants

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Helmut Sies¹•Institutions (1)

University of Düsseldorf¹

01 Mar 1997-Experimental Physiology

TL;DR: These low molecular mass antioxidant molecules add significantly to the defense provided by the enzymes superoxide dismutase, catalase and glutathione peroxidases, which are termed ‘oxidative stress’.

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Abstract: An imbalance between oxidants and antioxidants in favour of the oxidants, potentially leading to damage, is termed 'oxidative stress'. Oxidants are formed as a normal product of aerobic metabolism but can be produced at elevated rates under pathophysiological conditions. Antioxidant defense involves several strategies, both enzymatic and non-enzymatic. In the lipid phase, tocopherols and carotenes as well as oxy-carotenoids are of interest, as are vitamin A and ubiquinols. In the aqueous phase, there are ascorbate, glutathione and other compounds. In addition to the cytosol, the nuclear and mitochondrial matrices and extracellular fluids are protected. Overall, these low molecular mass antioxidant molecules add significantly to the defense provided by the enzymes superoxide dismutase, catalase and glutathione peroxidases.

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4,485 citations

"Clinical perspective on oxidative s..." refers background in this paper

...Because oxidative stress results from a pro- and antioxidative imbalance [15,16], current knowledge of intrinsic antioxidative mechanisms is reviewed along with possible interactions between oxidative...
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Journal Article•DOI•

Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS

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Mariely DeJesus-Hernandez¹, Ian R. A. Mackenzie², Bradley F. Boeve¹, Adam L. Boxer³, Matt Baker¹, Nicola J. Rutherford¹, Alexandra M. Nicholson¹, Ni Cole A. Finch¹, Heather C. Flynn¹, Jennifer Adamson¹, Naomi Kouri¹, Aleksandra Wojtas¹, Pheth Sengdy², Ging-Yuek Robin Hsiung², Anna Karydas³, William W. Seeley³, Keith A. Josephs¹, Giovanni Coppola⁴, Daniel H. Geschwind⁴, Zbigniew K. Wszolek¹, Howard Feldman², Howard Feldman⁵, David S. Knopman¹, Ronald C. Petersen¹, Bruce L. Miller³, Dennis W. Dickson¹, Kevin B. Boylan¹, Neill R. Graff-Radford¹, Rosa Rademakers¹ - Show less +25 more•Institutions (5)

Mayo Clinic¹, University of British Columbia², University of California, San Francisco³, Semel Institute for Neuroscience and Human Behavior⁴, Bristol-Myers Squibb⁵

20 Oct 2011-Neuron

TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.

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4,153 citations

"Clinical perspective on oxidative s..." refers background in this paper

...[8] DeJesus-Hernandez, M; Mackenzie, IR; Boeve, BF; Boxer, AL; Baker, M; Rutherford, NJ; Nicholson, AM; Finch, NA; Flynn, H; Adamson, J; Kouri, N; Wojtas, A; Sengdy, P; Hsiung, GY; Karydas, A; Seeley, WW; Josephs, KA; Coppola, G; Geschwind, DH; Wszolek, ZK; Feldman, H; Knopman, DS; Petersen, RC; Miller, BL; Dickson, DW; Boylan, KB; Graff-Radford, NR; Rademakers, R. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS....
[...]
...A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD....
[...]
...They account for approximately 15–20% of fALS cases, and thus SOD1 mutations are the second most frequent known cause of fALS after C9ORF72 [8,9,225]....
[...]
...[181] Murray, ME; DeJesus-Hernandez, M; Rutherford, NJ; Baker, M; Duara, R; Graff-Radford, NR; Wszolek, ZK; Ferman, TJ; Josephs, KA; Boylan, KB; Rademakers, R; Dickson, DW. Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72....
[...]

Journal Article•DOI•

A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD

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Alan E. Renton¹, Elisa Majounie¹, Adrian James Waite², Javier Simón-Sánchez³, Javier Simón-Sánchez⁴, Sara Rollinson⁵, J. Raphael Gibbs¹, J. Raphael Gibbs⁶, Jennifer C. Schymick¹, Hannu Laaksovirta⁷, John C. van Swieten⁴, John C. van Swieten³, Liisa Myllykangas⁷, Hannu Kalimo⁷, Anders Paetau⁷, Yevgeniya Abramzon¹, Anne M. Remes⁸, Alice Kaganovich¹, Sonja W. Scholz⁹, Sonja W. Scholz¹, Sonja W. Scholz¹⁰, Jamie Duckworth¹, Jinhui Ding¹, Daniel W. Harmer¹¹, Dena G. Hernandez⁶, Dena G. Hernandez¹, Janel O. Johnson¹, Janel O. Johnson⁶, Kin Y. Mok⁶, Mina Ryten⁶, Danyah Trabzuni⁶, Rita Guerreiro⁶, Richard W. Orrell⁶, James Neal², Alexandra Murray¹², J. P. Pearson², Iris E. Jansen³, David Sondervan³, Harro Seelaar⁴, Derek J. Blake², Kate Young⁵, Nicola Halliwell⁵, Janis Bennion Callister⁵, Greg Toulson⁵, Anna Richardson⁵, Alexander Gerhard⁵, Julie S. Snowden⁵, David M. A. Mann⁵, David Neary⁵, Mike A. Nalls¹, Terhi Peuralinna⁷, Lilja Jansson⁷, Veli-Matti Isoviita⁷, Anna-Lotta Kaivorinne⁸, Maarit Hölttä-Vuori⁷, Elina Ikonen⁷, Raimo Sulkava¹³, Michael Benatar¹⁴, Joanne Wuu¹⁴, Adriano Chiò¹⁵, Gabriella Restagno, Giuseppe Borghero¹⁶, Mario Sabatelli¹⁷, David Heckerman¹⁸, Ekaterina Rogaeva¹⁹, Lorne Zinman¹⁹, Jeffrey D. Rothstein⁹, Michael Sendtner²⁰, Carsten Drepper²⁰, Evan E. Eichler²¹, Can Alkan²¹, Ziedulla Abdullaev¹, Svetlana Pack¹, Amalia Dutra¹, Evgenia Pak¹, John Hardy⁶, Andrew B. Singleton¹, Nigel Williams², Peter Heutink³, Stuart Pickering-Brown⁵, Huw R. Morris²², Huw R. Morris¹², Huw R. Morris², Pentti J. Tienari⁷, Bryan J. Traynor¹, Bryan J. Traynor⁹ - Show less +82 more•Institutions (22)

National Institutes of Health¹, Cardiff University², VU University Amsterdam³, Erasmus University Rotterdam⁴, University of Manchester⁵, University College London⁶, University of Helsinki⁷, University of Oulu⁸, Johns Hopkins University⁹, Georgetown University¹⁰, Illumina¹¹, University Hospital of Wales¹², University of Eastern Finland¹³, University of Miami¹⁴, University of Turin¹⁵, University of Cagliari¹⁶, The Catholic University of America¹⁷, Microsoft¹⁸, University of Toronto¹⁹, University of Würzburg²⁰, University of Washington²¹, Aneurin Bevan University Health Board²²

20 Oct 2011-Neuron

TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.

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3,784 citations