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https://www.readbyqxmd.com/read/27915998/an-update-on-semantic-dementia-genetics-imaging-and-pathology
#1
REVIEW
Ramon Landin-Romero, Rachel Tan, John R Hodges, Fiona Kumfor
Progressive and relatively circumscribed loss of semantic knowledge, referred to as semantic dementia (SD) which falls under the broader umbrella of frontotemporal dementia, was officially identified as a clinical syndrome less than 50 years ago. Here, we review recent neuroimaging, pathological, and genetic research in SD. From a neuroimaging perspective, SD is characterised by hallmark asymmetrical atrophy of the anterior temporal pole and anterior fusiform gyrus, which is usually left lateralised. Functional magnetic resonance imaging (fMRI) studies have revealed widespread changes in connectivity, implicating the anterior temporal regions in semantic deficits in SD...
December 5, 2016: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/27871485/unusual-processing-generates-spa-lncrnas-that-sequester-multiple-rna-binding-proteins
#2
Huang Wu, Qing-Fei Yin, Zheng Luo, Run-Wen Yao, Chuan-Chuan Zheng, Jun Zhang, Jian-Feng Xiang, Li Yang, Ling-Ling Chen
We identify a type of polycistronic transcript-derived long noncoding RNAs (lncRNAs) that are 5' small nucleolar RNA (snoRNA) capped and 3' polyadenylated (SPAs). SPA processing is associated with nascent mRNA 3' processing and kinetic competition between XRN2 trimming and Pol II elongation. Following cleavage/polyadenylation of its upstream gene, the downstream uncapped pre-SPA is trimmed by XRN2 until this exonuclease reaches the co-transcriptionally assembled snoRNP. This snoRNP complex prevents further degradation, generates a snoRNA 5' end, and allows continuous Pol II elongation...
November 3, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27849576/two-familial-als-proteins-function-in-prevention-repair-of-transcription-associated-dna-damage
#3
Sarah J Hill, Daniel A Mordes, Lisa A Cameron, Donna S Neuberg, Serena Landini, Kevin Eggan, David M Livingston
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27767988/a-novel-loss-of-function-grn-mutation-p-tyr229-%C3%A2-clinical-and-neuropathological-features
#4
Liina Kuuluvainen, Minna Pöyhönen, Petra Pasanen, Maija Siitonen, Jaana Rummukainen, Pentti J Tienari, Anders Paetau, Liisa Myllykangas
Mutations in the progranulin (GRN) gene represent about 5-10% of frontotemporal lobar degeneration (FTLD). We describe a proband with a novel GRN mutation c.687T>A, p.(Tyr229*), presenting with dyspraxia, dysgraphia, and dysphasia at the age of 60 and a very severe FTLD neuropathological phenotype with TDP43 inclusions. The nephew of the proband had signs of dementia and personality changes at the age of 60 and showed similar but milder FTLD pathology. Three other family members had had early-onset dementia...
October 20, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27687581/sod1-dimerization-monitoring-using-a-novel-split-nanoluc-nanobit
#5
Kentaro Oh-Hashi, Yoko Hirata, Kazutoshi Kiuchi
In the present study, we applied a highly sensitive NanoLuc-based technology to understand the status of superoxide dismutase 1 (SOD1) within mammalian cells. Two fragments of NanoLuc (NanoBit), large N-terminal and small C-terminal regions, were fused with wild-type (wt) and mutant human SOD1 (hSOD1) genes and transfected into cells. Luciferase activity through NanoBit assembly was only detected in NanoBit-tagged wtSOD1-expressing cells. Furthermore, the developed NanoLuc system was used to investigate the role of protein-protein interactions in the pathogenesis of amyotrophic lateral sclerosis (ALS)...
October 2016: Cell Biochemistry and Function
https://www.readbyqxmd.com/read/27452472/in%C3%A2-vivo-formation-of-vacuolated-multi-phase-compartments-lacking-membranes
#6
Hermann Broder Schmidt, Rajat Rohatgi
Eukaryotic cells contain membrane-less organelles, including nucleoli and stress granules, that behave like liquid droplets. Such endogenous condensates often have internal substructure, but how this is established in the absence of membrane encapsulation remains unclear. We find that the N- and C-terminal domains of TDP43, a heterogeneous nuclear ribonucleoprotein implicated in neurodegenerative diseases, are capable of driving the formation of sub-structured liquid droplets in vivo. These droplets contain dynamic internal "bubbles" of nucleoplasm, reminiscent of membrane-based multi-vesicular endosomes...
August 2, 2016: Cell Reports
https://www.readbyqxmd.com/read/27324898/protein-profile-and-morphological-alterations-in-penumbra-after-focal-photothrombotic-infarction-in-the-rat-cerebral-cortex
#7
Anatoly Uzdensky, Svetlana Demyanenko, Grigory Fedorenko, Tayana Lapteva, Alexej Fedorenko
After ischemic stroke, cell damage propagates from infarct core to surrounding tissues (penumbra). To reveal proteins involved in neurodegeneration and neuroprotection in penumbra, we studied protein expression changes in 2-mm ring around the core of photothrombotic infarct induced in the rat brain cortex by local laser irradiation after administration of Bengal Rose. The ultrastructural study showed edema and degeneration of neurons, glia, and capillaries. Morphological changes gradually decreased across the penumbra...
June 21, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27318192/post-translational-protein-arginylation-in-the-normal-nervous-system-and-in-neurodegeneration
#8
REVIEW
Mauricio R Galiano, Victor E Goitea, Marta E Hallak
Post-translational arginylation of proteins is an important regulator of many physiological pathways in cells. This modification was originally noted in protein degradation during neurodegenerative processes, with an apparently different physiological relevance between central and peripheral nervous system. Subsequent studies have identified a steadily increasing number of proteins and proteolysis-derived polypeptides as arginyltransferase (ATE1) substrates, including β-amyloid, α-synuclein, and TDP43 proteolytic fragments...
August 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27239528/discriminative-and-prognostic-potential-of-cerebrospinal-fluid-phosphotau-tau-ratio-and-neurofilaments-for-frontotemporal-dementia-subtypes
#9
Yolande A L Pijnenburg, Nicolaas A Verwey, Wiesje M van der Flier, Philip Scheltens, Charlotte E Teunissen
INTRODUCTION: A decreased cerebrospinal fluid (CSF) p-Tau181 to total tau ratio (p/t-tau) is a biomarker for frontotemporal lobar degeneration with TDP43 inclusions (FTLD-TDP) and for amyotrophic lateral sclerosis (ALS). CSF light chain neurofilaments (NfL) are increased in ALS. We examined whether CSF p/t-tau and NfL are related to ALS status in FTLD-TDP. METHODS: We compared CSF p/t-tau and NfL levels between patients with FTLD-TDP with ALS (n = 15), FTLD-TDP without ALS (n = 17), FTLD-Tau (n = 6), Alzheimer's disease (AD; n = 25), and subjective memory complaints (SMC, n = 24)...
December 2015: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
https://www.readbyqxmd.com/read/27229480/proteomic-analysis-of-novel-targets-associated-with-the-enhancement-of-trka-induced-sk-n-mc-cancer-cell-death-caused-by-ngf
#10
Eun Joo Jung, Ky Hyun Chung, Dong-Won Bae, Choong Won Kim
Nerve growth factor (NGF) is known to regulate both cancer cell survival and death signaling, depending on the cellular circumstances, in various cell types. In this study, we showed that NGF strongly upregulated the protein level of tropomyosin-related kinase A (TrkA) in TrkA-inducible SK-N-MC cancer cells, resulting in increases in various TrkA-dependent cellular processes, including the phosphorylation of c-Jun N-terminal kinase (JNK) and caspase-8 cleavage. In addition, NGF enhanced TrkA-induced morphological changes and cell death, and this effect was significantly suppressed by the JNK inhibitor SP600125, but not by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin...
2016: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/27150074/oxidative-stress-and-mitochondrial-damage-in-the-pathogenesis-of-als-new-perspectives
#11
REVIEW
F Bozzo, A Mirra, M T Carrì
This review attempts to reconcile the present dual view of the mechanisms operating in Amyotrophic Lateral Sclerosis (ALS). On one side, oxidative stress, mitochondrial damage and protein aggregation are considered as causative of the disease, as strongly supported by evidence obtained in models based on the expression of ALS-typical mutant SOD1. On the other hand, evidence from models expressing ALS-typical mutations in RNA-binding proteins such as FUS and TDP43 indicate that mRNA (dys)metabolism is a major pathway in this disease...
January 1, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/27110240/structural-dynamics-of-human-argonaute2-and-its-interaction-with-sirnas-designed-to-target-mutant-tdp43
#12
Vishwambhar Bhandare, Amutha Ramaswamy
The human Argonaute2 protein (Ago2) is a key player in RNA interference pathway and small RNA recognition by Ago2 is the crucial step in siRNA mediated gene silencing mechanism. The present study highlights the structural and functional dynamics of human Ago2 and the interaction mechanism of Ago2 with a set of seven siRNAs for the first time. The human Ago2 protein adopts two conformations such as "open" and "close" during the simulation of 25 ns. One of the domains named as PAZ, which is responsible for anchoring the 3'-end of siRNA guide strand, is observed as a highly flexible region...
2016: Advances in Bioinformatics
https://www.readbyqxmd.com/read/26979082/altered-proteins-in-the-aging-brain
#13
Adila Elobeid, Sylwia Libard, Marina Leino, Svetlana N Popova, Irina Alafuzoff
We assessed the prevalence of common altered brain proteins in 296 cognitively unimpaired subjects ranging from age 50 to 102 years. The incidence and the stage of hyperphosphorylated-τ (HPτ), β-amyloid, α-synuclein (αS), and transactive response DNA (TDP) binding protein 43 (TDP43)-immunoreactivity (-IR) increased with age. HPτ-IR was observed in 98% of the subjects; the locus coeruleus was solely affected in 46%, and 79% of the subjects were in Braak stages a to II. β-Amyloid was seen in 47% of subjects and the Thal phase correlated with the HPτ Braak stage and age...
April 2016: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/26902425/high-tdp43-expression-is-required-for-trim16-induced-inhibition-of-cancer-cell-growth-and-correlated-with-good-prognosis-of-neuroblastoma-and-breast-cancer-patients
#14
Patrick Y Kim, Owen Tan, Bing Liu, Toby Trahair, Tao Liu, Michelle Haber, Murray D Norris, Glenn M Marshall, Belamy B Cheung
Tripartite Motif-containing protein 16 (TRIM16) is a member of a large family of tripartite motif (TRIM) proteins, that has been implicated in the pathogenesis of multiple cancers. However, the mechanism by which TRIM16 acts as a tumour suppressor is currently unknown. We used the versatile yeast two-hybrid assay on a cDNA library from human testes, which has relative high TRIM16 expression, to identify potential TRIM16-binding proteins. We identified transactive response DNA-binding protein 43 (TDP43) as a novel TRIM16 binding protein...
May 1, 2016: Cancer Letters
https://www.readbyqxmd.com/read/26854610/identification-of-possible-sirna-molecules-for-tdp43-mutants-causing-amyotrophic-lateral-sclerosis-in-silico-design-and-molecular-dynamics-study
#15
Vishwambhar Vishnu Bhandare, Amutha Ramaswamy
The DNA binding protein, TDP43 is a major protein involved in amyotrophic lateral sclerosis and other neurological disorders such as frontotemporal dementia, Alzheimer disease, etc. In the present study, we have designed possible siRNAs for the glycine rich region of tardbp mutants causing ALS disorder based on a systematic theoretical approach including (i) identification of respective codons for all mutants (reported at the protein level) based on both minimum free energy and probabilistic approaches, (ii) rational design of siRNA, (iii) secondary structure analysis for the target accessibility of siRNA, (iii) determination of the ability of siRNA to interact with mRNA and the formation/stability of duplex via molecular dynamics study for a period of 15ns and (iv) characterization of mRNA-siRNA duplex stability based on thermo-physical analysis...
April 2016: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/26728149/pur-alpha-regulates-cytoplasmic-stress-granule-dynamics-and-ameliorates-fus-toxicity
#16
J Gavin Daigle, Karthik Krishnamurthy, Nandini Ramesh, Ian Casci, John Monaghan, Kevin McAvoy, Earl W Godfrey, Dianne C Daniel, Edward M Johnson, Zachary Monahan, Frank Shewmaker, Piera Pasinelli, Udai Bhan Pandey
Amyotrophic lateral sclerosis is characterized by progressive loss of motor neurons in the brain and spinal cord. Mutations in several genes, including FUS, TDP43, Matrin 3, hnRNPA2 and other RNA-binding proteins, have been linked to ALS pathology. Recently, Pur-alpha, a DNA/RNA-binding protein was found to bind to C9orf72 repeat expansions and could possibly play a role in the pathogenesis of ALS. When overexpressed, Pur-alpha mitigates toxicities associated with Fragile X tumor ataxia syndrome (FXTAS) and C9orf72 repeat expansion diseases in Drosophila and mammalian cell culture models...
April 2016: Acta Neuropathologica
https://www.readbyqxmd.com/read/26493020/replication-study-of-matr3-in-familial-and-sporadic-amyotrophic-lateral-sclerosis
#17
Claire S Leblond, Ziv Gan-Or, Dan Spiegelman, Sandra B Laurent, Anna Szuto, Alan Hodgkinson, Alexandre Dionne-Laporte, Pierre Provencher, Mamede de Carvalho, Sandro Orrù, Denis Brunet, Jean-Pierre Bouchard, Philip Awadalla, Nicolas Dupré, Patrick A Dion, Guy A Rouleau
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by an extensive loss of motor neurons in the primary motor cortex, brainstem, and spinal cord. Genetic studies report a high heritability of ALS. Recently, whole-exome sequencing analysis of familial ALS (FALS) patients allowed the identification of missense variations within the MATR3 gene. MATR3 was previously associated to distal myopathy 2 and encodes for a nuclear matrix and DNA/RNA binding protein that has been shown to interact with TDP43 in an RNA-dependent manner...
January 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/26265046/regulation-of-malat1-expression-by-tdp43-controls-the-migration-and-invasion-of-non-small-cell-lung-cancer-cells-in%C3%A2-vitro
#18
Fengjie Guo, Feng Jiao, Zuoqing Song, Shujun Li, Bin Liu, Hongwei Yang, Qinghua Zhou, Zhigang Li
MALAT1 is a non-coding RNA overexpressed in non-small cell lung cancer (NSCLC). TDP-43 is a ubiquitously expressed, MALAT1-binding protein implicated in cancer development. We hypothesized that MALAT1 expression level is regulated in lung cancer by TDP-43. We analyzed their functions in cultured NSCLC cells. Downregulation of MALAT1 or TDP-43 expression by siRNA not only markedly suppressed NSCLC cell growth, as measured by the MTT assay in vitro cultured NSCLC cells (P < 0.05), but also noticeably impaired the migration and invasion of NSCLC cells, as analyzed by the migration and invasion assay...
September 18, 2015: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/26239295/tau-hyperphosphorylation-in-synaptosomes-and-neuroinflammation-are-associated-with-canine-cognitive-impairment
#19
Tomas Smolek, Aladar Madari, Jana Farbakova, Ondrej Kandrac, Santosh Jadhav, Martin Cente, Veronika Brezovakova, Michal Novak, Norbert Zilka
Canine cognitive impairment syndrome (CDS) represents a group of symptoms related to the aging of the canine brain. These changes ultimately lead to a decline of memory function and learning abilities, alteration of social interaction, impairment of normal housetraining, and changes in sleep-wake cycle and general activity. We have clinically examined 215 dogs, 28 of which underwent autopsy. With canine brains, we performed extensive analysis of pathological abnormalities characteristic of human Alzheimer's disease and frontotemporal lobar degeneration, including β-amyloid senile plaques, tau neurofibrillary tangles, and fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP43) inclusions...
March 1, 2016: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/26136049/degeneration-of-proprioceptive-sensory-nerve-endings-in-mice-harboring-amyotrophic-lateral-sclerosis-causing-mutations
#20
Sydney K Vaughan, Zachary Kemp, Theo Hatzipetros, Fernando Vieira, Gregorio Valdez
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily targets the motor system. Although much is known about the effects of ALS on motor neurons and glial cells, little is known about its effect on proprioceptive sensory neurons. This study examines proprioceptive sensory neurons in mice harboring mutations associated with ALS, in SOD1(G93A) and TDP43(A315T) transgenic mice. In both transgenic lines, we found fewer proprioceptive sensory neurons containing fluorescently tagged cholera toxin in their soma five days after injecting this retrograde tracer into the tibialis anterior muscle...
December 1, 2015: Journal of Comparative Neurology
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