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https://www.readbyqxmd.com/read/29155947/dementia-after-moderate-severe-traumatic-brain-injury-coexistence-of-multiple-proteinopathies
#1
Kimbra Kenney, Diego Iacono, Brian L Edlow, Douglas I Katz, Ramon Diaz-Arrastia, Kristen Dams-O'Connor, Daniel H Daneshvar, Allison Stevens, Allison L Moreau, Lee S Tirrell, Ani Varjabedian, Anastasia Yendiki, Andre van der Kouwe, Azma Mareyam, Jennifer A McNab, Wayne A Gordon, Bruce Fischl, Ann C McKee, Daniel P Perl
We report the clinical, neuroimaging, and neuropathologic characteristics of 2 patients who developed early onset dementia after a moderate-severe traumatic brain injury (TBI). Neuropathological evaluation revealed abundant β-amyloid neuritic and cored plaques, diffuse β-amyloid plaques, and frequent hyperphosphorylated-tau neurofibrillary tangles (NFT) involving much of the cortex, including insula and mammillary bodies in both cases. Case 1 additionally showed NFTs in both the superficial and deep cortical layers, occasional perivascular and depth-of-sulci NFTs, and parietal white matter rarefaction, which corresponded with decreased parietal fiber tracts observed on ex vivo MRI...
November 16, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/29153610/tdp-43-proteolysis-is-associated-with-astrocyte-reactivity-after-traumatic-brain-injury-in-rodents
#2
Chih-Yuan Huang, Yi-Che Lee, Ping-Chia Li, Po-Chou Liliang, Kang Lu, Kuo-Wei Wang, Li-Ching Chang, Li-Yen Shiu, Ming-Feng Chen, Yuan-Ting Sun, Hao-Kuang Wang
The aggregation and deposition of transactivation response DNA-binding protein 43 (TDP-43) in neurons and astrocytes is characteristic in a number of neurodegenerative diseases including Alzheimer's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Nevertheless, the exact role of TDP-43 in astrocytes is unknown. Recently, TDP-43 was identified in neurons but not astrocytes after traumatic brain injury (TBI) in humans. In the present study, we evaluated TDP-43 expression and proteolysis in astrocytes in a rat model of TBI...
December 15, 2017: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/29153328/tdp-43-promotes-neurodegeneration-by-impairing-chromatin-remodeling
#3
Amit Berson, Ashley Sartoris, Raffaella Nativio, Vivianna Van Deerlin, Jon B Toledo, Sílvia Porta, Shichong Liu, Chia-Yu Chung, Benjamin A Garcia, Virginia M-Y Lee, John Q Trojanowski, F Brad Johnson, Shelley L Berger, Nancy M Bonini
Regulation of chromatin structure is critical for brain development and function. However, the involvement of chromatin dynamics in neurodegeneration is less well understood. Here we find, launching from Drosophila models of amyotrophic lateral sclerosis and frontotemporal dementia, that TDP-43 impairs the induction of multiple key stress genes required to protect from disease by reducing the recruitment of the chromatin remodeler Chd1 to chromatin. Chd1 depletion robustly enhances TDP-43-mediated neurodegeneration and promotes the formation of stress granules...
November 9, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/29142232/tdp-43-misexpression-causes-defects-in-dendritic-growth
#4
Josiah J Herzog, Mugdha Deshpande, Leah Shapiro, Avital A Rodal, Suzanne Paradis
Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) share overlapping genetic causes and disease symptoms, and are linked neuropathologically by the RNA binding protein TDP-43 (TAR DNA binding protein-43 kDa). TDP-43 regulates RNA metabolism, trafficking, and localization of thousands of target genes. However, the cellular and molecular mechanisms by which dysfunction of TDP-43 contributes to disease pathogenesis and progression remain unclear. Severe changes in the structure of neuronal dendritic arbors disrupt proper circuit connectivity, which in turn could contribute to neurodegenerative disease...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29136240/postmortem-autopsy-confirmation-of-antemortem-f-18-fddnp-pet-scans-in-a-football-player-with-chronic-traumatic-encephalopathy
#5
Bennet Omalu, Gary W Small, Julian Bailes, Linda M Ercoli, David A Merrill, Koon-Pong Wong, Sung-Cheng Huang, Nagichettiar Satyamurthy, Jennifer L Hammers, John Lee, Robert P Fitzsimmons, Jorge R Barrio
Currently, only presumptive diagnosis of chronic traumatic encephalopathy (CTE) can be made in living patients. We present a modality that may be instrumental to the definitive diagnosis of CTE in living patients based on brain autopsy confirmation of [F-18]FDDNP-PET findings in an American football player with CTE. [F-18]FDDNP-PET imaging was performed 52 mo before the subject's death. Relative distribution volume parametric images and binding values were determined for cortical and subcortical regions of interest...
November 10, 2017: Neurosurgery
https://www.readbyqxmd.com/read/29134465/current-role-for-biomarkers-in-clinical-diagnosis-of-alzheimer-disease-and-frontotemporal-dementia
#6
REVIEW
Nasim Sheikh-Bahaei, Seyed Ahmad Sajjadi, Aimee L Pierce
Purpose of review Alzheimer's disease (AD) and frontotemporal dementia can often be diagnosed accurately with careful clinical history, cognitive testing, neurological examination, and structural brain MRI. However, there are certain circumstances wherein detection of specific biomarkers of neurodegeneration or underlying AD pathology will impact the clinical diagnosis or treatment plan. We will review the currently available biomarkers for AD and frontotemporal dementia (FTD) and discuss their clinical importance...
November 14, 2017: Current Treatment Options in Neurology
https://www.readbyqxmd.com/read/29134321/co-occurrence-of-mixed-proteinopathies-in-late-stage-huntington-s-disease
#7
Isabelle St-Amour, Andréanne Turgeon, Claudia Goupil, Emmanuel Planel, Sébastien S Hébert
Accumulating evidence highlights the potential role of mixed proteinopathies (i.e., abnormal protein aggregation) in the development of clinical manifestations of neurodegenerative diseases (NDD). Huntington's disease (HD) is an inherited NDD caused by autosomal-dominant expanded CAG trinucleotide repeat mutation in the gene coding for Huntingtin (Htt). Previous studies have suggested the coexistence of phosphorylated-Tau, α-synuclein (α-Syn) and TAR DNA-binding protein 43 (TDP-43) inclusions in HD. However, definite evidence that HD pathology in humans can be accompanied by other proteinopathies is still lacking...
November 13, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/29134122/platelet-phosphorylated-tdp-43-an-exploratory-study-for-a-peripheral-surrogate-biomarker-development-for-alzheimer-s-disease
#8
Rodger Wilhite, Jessica M Sage, Abdurrahman Bouzid, Tyler Primavera, Abdulbaki Agbas
Aim: Alzheimer's disease (AD) and other forms of dementia create a noncurable disease population in world's societies. To develop a blood-based biomarker is important so that the remedial or disease-altering therapeutic intervention for AD patients would be available at the early stage. Materials & methods: TDP-43 levels were analyzed in postmortem brain tissue and platelets of AD and control subjects. Results: We observed an increased TDP-43 (<60%) in postmortem AD brain regions and similar trends were also observed in patient's platelets...
November 2017: Future Science OA
https://www.readbyqxmd.com/read/29128563/matrin-3-is-a-component-of-neuronal-cytoplasmic-inclusions-of-motor-neurons-in-sporadic-amyotrophic-lateral-sclerosis
#9
Mikiko Tada, Hiroshi Doi, Shigeru Koyano, Shun Kubota, Ryoko Fukai, Shunta Hashiguchi, Noriko Hayashi, Yuko Kawamoto, Misako Kunii, Kenichi Tanaka, Keita Takahashi, Yuki Ogawa, Ryo Iwata, Shoji Yamanaka, Hideyuki Takeuchi, Fumiaki Tanaka
Mutations in the matrin 3 (MATR3) gene have been identified as a cause of familial amyotrophic lateral sclerosis, but the involvement of MATR3 protein in sporadic amyotrophic lateral sclerosis (SALS) pathology has not been fully assessed. Here, we immunohistochemically analyzed MATR3 pathology in the spinal cords of SALS and control autopsies. MATR3 immunostaining of the motor neuron nuclei revealed two distinct patterns, mild and strong staining. There were no differences in the ratio of mild versus strong nuclear staining between the SALS and control cases...
November 8, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/29125873/u6-snrna-expression-prevents-toxicity-in-tdp-43-knockdown-cells
#10
Masao Yahara, Akira Kitamura, Masataka Kinjo
Depletion of amyotrophic lateral sclerosis (ALS)-associated transactivation response (TAR) RNA/DNA-binding protein 43 kDa (TDP-43) alters splicing efficiency of multiple transcripts and results in neuronal cell death. TDP-43 depletion can also disturb expression levels of small nuclear RNAs (snRNAs) as spliceosomal components. Despite this knowledge, the relationship between cell death and alteration of snRNA expression during TDP-43 depletion remains unclear. Here, we knocked down TDP-43 in murine neuroblastoma Neuro2A cells and found a time lag between efficient TDP-43 depletion and appearance of cell death, suggesting that several mechanisms mediate between these two events...
2017: PloS One
https://www.readbyqxmd.com/read/29115989/clusterin-protects-neurons-against-intracellular-proteotoxicity
#11
Jenna M Gregory, Daniel R Whiten, Rebecca A Brown, Teresa P Barros, Janet R Kumita, Justin J Yerbury, Sandeep Satapathy, Karina McDade, Colin Smith, Leila M Luheshi, Christopher M Dobson, Mark R Wilson
It is now widely accepted in the field that the normally secreted chaperone clusterin is redirected to the cytosol during endoplasmic reticulum (ER) stress, although the physiological function(s) of this physical relocation remain unknown. We have examined in this study whether or not increased expression of clusterin is able to protect neuronal cells against intracellular protein aggregation and cytotoxicity, characteristics that are strongly implicated in a range of neurodegenerative diseases. We used the amyotrophic lateral sclerosis-associated protein TDP-43 as a primary model to investigate the effects of clusterin on protein aggregation and neurotoxicity in complementary in vitro, neuronal cell and Drosophila systems...
November 7, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29110334/frontotemporal-dementia-with-trans-activation-response-dna-binding-protein-43-presenting-with-catatonic-syndrome
#12
Ryohei Watanabe, Ito Kawakami, Mitsumoto Onaya, Shinji Higashi, Nobutaka Arai, Haruhiko Akiyama, Masato Hasegawa, Tetsuaki Arai
Catatonia is a clinical syndrome characterized by symptoms such as immobility, mutism, stupor, stereotypy, echophenomena, catalepsy, automatic obedience, posturing, negativism, gegenhalten and ambitendency. This syndrome occurs mostly in mood disorder and schizophrenic patients, and is related to neuronal dysfunction involving the frontal lobe. Some cases of frontotemporal dementia (FTD) with catatonia have been reported, but these cases were not examined by autopsy. Here, we report on a FTD case which showed catatonia after the first episode of brief psychotic disorder...
November 7, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/29109432/als-associated-mutations-in-matrin-3-alter-protein-protein-interactions-and-impede-mrna-nuclear-export
#13
Ashley Boehringer, Krystine Garcia-Mansfield, Gurkaran Singh, Nadine Bakkar, Patrick Pirrotte, Robert Bowser
Mutations in Matrin 3 have recently been linked to ALS, though the mechanism that induces disease in these patients is unknown. To define the protein interactome of wild-type and ALS-linked MATR3 mutations, we performed immunoprecipitation followed by mass spectrometry using NSC-34 cells expressing human wild-type or mutant Matrin 3. Gene ontology analysis identified a novel role for Matrin 3 in mRNA transport centered on proteins in the TRanscription and EXport (TREX) complex, known to function in mRNA biogenesis and nuclear export...
November 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29109149/chronic-oxidative-stress-promotes-gadd34-mediated-phosphorylation-of-the-tar-dna-binding-protein-tdp-43-a-modification-linked-to-neurodegeneration
#14
Catherine Wenhui Goh, Irene Chengjie Lee, Jeyapriya Rajameenakshi Sundaram, Simi Elizabeth George, Permeen Yusoff, Matthew Hayden Brush, Newman Siu Kwan Sze, Shirish Shenolikar
Oxidative and endoplasmic reticulum (ER) stresses are hallmarks of the pathophysiology of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. In these stresses, different kinases phosphorylate eukaryotic initiation factor eIF2α enabling the translation of stress response genes, among these is GADD34, the protein product of which recruits the α-isoform of protein phosphatase 1 catalytic subunit (PP1α) and eIF2α to assemble a phosphatase complex catalyzing eIF2α dephosphorylation and resumption of protein synthesis...
November 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29109084/ubiquitin-binding-protein-cg5445-suppresses-aggregation-and-cytotoxicity-of-amyotrophic-lateral-sclerosis-linked-tdp-43-in-drosophila
#15
Hiroyuki Uechi, Erina Kuranaga, Tomohiro Iriki, Kohei Takano, Shoshiro Hirayama, Masayuki Miura, Jun Hamazaki, Shigeo Murata
Ubiquitin-mediated protein degradation plays essential roles in proteostasis and is involved in the pathogenesis of neurodegenerative diseases in which ubiquitin-positive aberrant proteins accumulate. However, how such aberrant proteins are processed inside cells has not been fully explored. Here, we show that the product of CG5445, a previously uncharacterized Drosophila gene, prevents accumulation of aggregate-prone ubiquitinated proteins. We found that ubiquitin conjugates were associated with CG5445, knockdown of which caused accumulation of detergent-insoluble ubiquitinated proteins...
November 6, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29097807/tdp-43-accelerates-age-dependent-degeneration-of-interneurons
#16
Hitomi Tsuiji, Ikuyo Inoue, Mari Takeuchi, Asako Furuya, Yuko Yamakage, Seiji Watanabe, Masato Koike, Mitsuharu Hattori, Koji Yamanaka
TDP-43 is an RNA-binding protein important for many aspects of RNA metabolism. Abnormal accumulation of TDP-43 in the cytoplasm of affected neurons is a pathological hallmark of the neurodegenerative diseases frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Several transgenic mouse models have been generated that recapitulate defects in TDP-43 accumulation, thus causing neurodegeneration and behavioural impairments. While aging is the key risk factor for neurodegenerative diseases, the specific effect of aging on phenotypes in TDP-43 transgenic mice has not been investigated...
November 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29089398/establishing-diagnostic-criteria-for-perry-syndrome
#17
Takayasu Mishima, Shinsuke Fujioka, Hiroyuki Tomiyama, Ichiro Yabe, Ryoichi Kurisaki, Naoki Fujii, Ryuji Neshige, Owen A Ross, Matthew J Farrer, Dennis W Dickson, Zbigniew K Wszolek, Nobutaka Hattori, Yoshio Tsuboi
OBJECTIVE: To establish international diagnostic criteria for Perry syndrome, a disorder characterised by clinical signs of parkinsonism, depression/apathy, weight loss, respiratory symptoms, mutations in the DCTN1 gene and TAR DNA-binding protein 43 (TDP-43) pathology. METHODS: Data from the published literature and newly identified patients were gathered and analysed during and after the International Symposium on Perry syndrome in Tokyo to identify diagnostic criteria for Perry syndrome...
October 31, 2017: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/29079747/disulfide-cross-linked-multimers-of-tdp-43-and-spinal-motoneuron%C3%A2-loss-in-a-tdp-43-a315t-als-ftd-mouse-model
#18
Leslie Bargsted, Danilo B Medinas, Francisca Martínez Traub, Pablo Rozas, Natalia Muñoz, Melissa Nassif, Carolina Jerez, Alejandra Catenaccio, Felipe A Court, Claudio Hetz, Soledad Matus
Tar DNA binding protein 43 (TDP-43) is the principal component of ubiquitinated protein inclusions present in nervous tissue of most cases of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previous studies described a TDP-43(A315T) transgenic mouse model that develops progressive motor dysfunction in the absence of protein aggregation or significant motoneuron loss, questioning its validity to study ALS. Here we have further characterized the course of the disease in TDP-43(A315T) mice using a battery of tests and biochemical approaches...
October 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29078806/distinct-tdp-43-inclusion-morphologies-in-frontotemporal-lobar-degeneration-with-and-without-amyotrophic-lateral-sclerosis
#19
Rachel H Tan, Yue Yang, Woojin S Kim, Carol Dobson-Stone, John B Kwok, Matthew C Kiernan, Glenda M Halliday
The identification of the TAR DNA-binding protein 43 (TDP-43) as the ubiquitinated cytoplasmic inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) confirmed that these two diseases share similar mechanisms, likely to be linked to the abnormal hyperphosphorylation, ubiquitination and cleavage of pathological TDP-43. Importantly however, a quantitative analysis of TDP-43 inclusions in predilection cortical regions of FTLD, FTLD-ALS and ALS cases has not been undertaken...
October 27, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29075249/human-endogenous-retrovirus-k-and-tdp-43-expression-bridges-als-and-hiv-neuropathology
#20
Renée N Douville, Avindra Nath
Despite the repetitive association of endogenous retroviruses in human disease, the mechanisms behind their pathological contributions remain to be resolved. Here we discuss how neuronal human endogenous retrovirus-K (HERV-K) expression in human immunodeficiency virus (HIV)-infected individuals is a distinct pathological aspect of HIV-associated neurological conditions, such as HIV encephalitis and HIV-associated neurocognitive disorders. Enhanced neuronal HERV-K levels were observed in the majority of HIV-infected individuals, and to a higher degree in brain tissue marked by HIV replication...
2017: Frontiers in Microbiology
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