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https://www.readbyqxmd.com/read/29313812/pathogenic-commonalities-between-spinal-muscular-atrophy-and-amyotrophic-lateral-sclerosis-converging-roads-to-therapeutic-development
#1
REVIEW
Melissa Bowerman, Lyndsay M Murrray, Frédérique Scamps, Bernard L Schneider, Rashmi Kothary, Cédric Raoul
Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are the two most common motoneuron disorders, which share typical pathological hallmarks while remaining genetically distinct. Indeed, SMA is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene whilst ALS, albeit being mostly sporadic, can also be caused by mutations within genes, including superoxide dismutase 1 (SOD1), Fused in Sarcoma (FUS), TAR DNA-binding protein 43 (TDP-43) and chromosome 9 open reading frame 72 (C9ORF72)...
December 4, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/29313467/temporal-expression-of-mutant-tdp-43-correlates-with-early-amyotrophic-lateral-sclerosis-phenotype-and-motor-weakness
#2
Qihua Chen, Jinxia Zhou, Cao Huang, Bo Huang, Fangfang Bi, Hongxia Zhou, Bo Xiao
BACKGROUND: Mutant transactive response DNA-binding protein (TDP-43) is closely correlated to inherited form of amyotrophic lateral sclerosis (ALS). TDP-43 transgenic rats can reproduce the core phenotype of ALS and constitutive expression of TDP-43 caused postnatal death. OBJECTIVE: To understand whether neurologic deficiency caused by mutant TDP-43 is dependent on its temporal expression. METHOD: Transgenic rats were established that express mutant human TDP-43 (M337V substitution) in neurons, then a Tet-off system was used to regulate its expression...
January 9, 2018: Current Neurovascular Research
https://www.readbyqxmd.com/read/29311743/tdp-43-pathology-disrupts-nuclear-pore-complexes-and-nucleocytoplasmic-transport-in-als-ftd
#3
Ching-Chieh Chou, Yi Zhang, Mfon E Umoh, Spencer W Vaughan, Ileana Lorenzini, Feilin Liu, Melissa Sayegh, Paul G Donlin-Asp, Yu Han Chen, Duc M Duong, Nicholas T Seyfried, Maureen A Powers, Thomas Kukar, Chadwick M Hales, Marla Gearing, Nigel J Cairns, Kevin B Boylan, Dennis W Dickson, Rosa Rademakers, Yong-Jie Zhang, Leonard Petrucelli, Rita Sattler, Daniela C Zarnescu, Jonathan D Glass, Wilfried Rossoll
The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery...
January 8, 2018: Nature Neuroscience
https://www.readbyqxmd.com/read/29308690/overexpression-of-a-conserved-hsp40-chaperone-reduces-toxicity-of-several-neurodegenerative-disease-proteins
#4
Sei-Kyoung Park, Fatih Arslan, Vydehi Kanneganti, Sami J Barmada, Pravinkumar Purushothaman, Subhash Chandra Verma, Susan W Liebman
TDP-43 and FUS are DNA/RNA binding proteins associated with neuronal inclusions in amyotrophic lateral sclerosis (ALS) patients. Other neurodegenerative diseases are also characterized by neuronal protein aggregates, e.g. Huntington's disease, associated with polyglutamine (polyQ) expansions in the protein huntingtin. Here we discuss our recent paper establishing similarities between aggregates of TDP-43 that have short glutamine and asparagine (Q/N)-rich modules and are soluble in detergents, with those of polyQ and PIN4C that have large Q/N-rich domains and are detergent-insoluble...
January 8, 2018: Prion
https://www.readbyqxmd.com/read/29305438/asymmetric-tdp-pathology-in-primary-progressive-aphasia-with-right-hemisphere-language-dominance
#5
Garam Kim, Shahrooz Vahedi, Tamar Gefen, Sandra Weintraub, Eileen H Bigio, Marek-Marsel Mesulam, Changiz Geula
OBJECTIVE: To quantitatively examine the regional densities and hemispheric distribution of the 43-kDa transactive response DNA-binding protein (TDP-43) inclusions, neurons, and activated microglia in a left-handed patient with right hemisphere language dominance and logopenic-variant primary progressive aphasia (PPA). METHODS: Phosphorylated TDP-43 inclusions, neurons, and activated microglia were visualized with immunohistochemical and histologic methods. Markers were quantified bilaterally with unbiased stereology in language- and memory-related cortical regions...
January 5, 2018: Neurology
https://www.readbyqxmd.com/read/29299811/impaired-cu-zn-superoxide-dismutase-sod1-and-calcineurin-cn-interaction-in-als-a-presumed-consequence-for-tdp-43-and-zinc-aggregation-in-tg-sod1g93a-rodent-spinal-cord-tissue
#6
Jolene M Kim, Elizabeth Billington, Ada Reyes, Tara Notarianni, Jessica Sage, Emre Agbas, Michael Taylor, Ian Monast, John A Stanford, Abdulbaki Agbas
Impaired interactions between Calcineurin (Cn) and (Cu/Zn) superoxide dismutase (SOD1) are suspected to be responsible for the formation of hyperphosphorylated protein aggregation in amyotrophic lateral sclerosis (ALS). Serine (Ser)- enriched phosphorylated TDP-43 protein aggregation appears in the spinal cord of ALS animal models, and may be linked to the reduced phosphatase activity of Cn. The mutant overexpressed SOD1G93A protein does not properly bind zinc (Zn) in animal models; hence, mutant SOD1G93A-Cn interaction weakens...
January 3, 2018: Neurochemical Research
https://www.readbyqxmd.com/read/29295857/defects-in-synaptic-transmission-at-the-neuromuscular-junction-precedes-motor-deficits-in-a-tdp-43q331k-transgenic-mouse-model-of-amyotrophic-lateral-sclerosis
#7
Kirat K Chand, Kah Meng Lee, John D Lee, Hao Qiu, Emily F Willis, Nickolas A Lavidis, Massimo A Hilliard, Peter G Noakes
Transactive response DNA-binding protein-43 (TDP-43) is involved in gene regulation via the control of RNA transcription, splicing, and transport. TDP-43 is a major protein component of ubiquinated inclusions that are found in amyotrophic lateral sclerosis (ALS); however, the function of TDP-43 at the neuromuscular junction (NMJ) and its role in ALS pathogenesis is largely unknown. Here, we show that TDP-43Q331K mutation in mice resulted in impaired neurotransmission by age 3 mo, preceding deficits in motor function and motor neuron loss, which were observed from age 10 mo...
January 2, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29286334/a-single-neonatal-exposure-to-bmaa-in-a-rat-model-produces-neuropathology-consistent-with-neurodegenerative-diseases
#8
Laura Louise Scott, Timothy Grant Downing
Although cyanobacterial β-N-methylamino-l-alanine (BMAA) has been implicated in the development of Alzheimer's Disease (AD), Parkinson's Disease (PD) and Amyotrophic Lateral Sclerosis (ALS), no BMAA animal model has reproduced all the neuropathology typically associated with these neurodegenerative diseases. We present here a neonatal BMAA model that causes β-amyloid deposition, neurofibrillary tangles of hyper-phosphorylated tau, TDP-43 inclusions, Lewy bodies, microbleeds and microgliosis as well as severe neuronal loss in the hippocampus, striatum, substantia nigra pars compacta, and ventral horn of the spinal cord in rats following a single BMAA exposure...
December 29, 2017: Toxins
https://www.readbyqxmd.com/read/29282338/unaffected-mosaic-c9orf72-case-rna-foci-dipeptide-proteins-but-upregulated-c9orf72-expression
#9
Philip McGoldrick, Ming Zhang, Marka van Blitterswijk, Christine Sato, Danielle Moreno, Shangxi Xiao, Ashley B Zhang, Paul M McKeever, Anna Weichert, Raphael Schneider, Julia Keith, Leonard Petrucelli, Rosa Rademakers, Lorne Zinman, Janice Robertson, Ekaterina Rogaeva
OBJECTIVE: Suggested C9orf72 disease mechanisms for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration include C9orf72 haploinsufficiency, G4C2/C4G2 RNA foci, and dipeptide repeat (DPR) proteins translated from the G4C2 expansion; however, the role of small expansions (e.g., 30-90 repeats) is unknown and was investigated here. METHODS: We conducted a molecular and pathology study of a family in which the father (unaffected at age 90) carried a 70-repeat allele in blood DNA that expanded to ≈1,750 repeats in his children, causing ALS...
December 27, 2017: Neurology
https://www.readbyqxmd.com/read/29279008/comparative-analysis-of-thermal-unfolding-simulations-of-rna-recognition-motifs-rrms-of-tar-dna-binding-protein-43-tdp-43
#10
Amresh Prakash, Vijay Kumar, Naveen Kumar Meena, Md Imtaiyaz Hassan, Andrew M Lynn
TAR DNA-binding protein 43 (TDP-43) inclusions have been found in Amyotrophic lateral sclerosis (ALS) and several other neurodegenerative diseases. Many studies suggest the involvement of RNA recognition motifs (RRMs) in TDP-43 proteinopathy. To elucidate the structural stability and the unfolding dynamics of RRMs, we have carried out atomistic molecular dynamics simulations at two different temperatures (300 K and 500 K). The simulations results indicate that there are distinct structural differences in the unfolding pathway between the two domains and RRM1 unfolds faster than RRM2 in accordance with the lower thermal stability found experimentally...
December 26, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29278558/autopsy-of-an-elderly-man-with-incidentally-diagnosed-tdp-43-proteinopathy
#11
Yukiko Hata, Koji Yoshida, Naoki Nishida
No abstract text is available yet for this article.
December 22, 2017: Alzheimer Disease and Associated Disorders
https://www.readbyqxmd.com/read/29273399/behavioral-defects-in-a-dctn1g71a-transgenic-mouse-model-of-perry-syndrome
#12
Takayasu Mishima, Manami Deshimaru, Takuya Watanabe, Kaori Kubota, Mariko Kinoshita-Kawada, Junichi Yuasa-Kawada, Kotaro Takasaki, Yoshinari Uehara, Shozo Jinno, Katsunori Iwasaki, Yoshio Tsuboi
Perry syndrome is a rare neurodegenerative disease characterized by parkinsonism, depression/apathy, weight loss, and central hypoventilation. Our previously-conducted genome-wide association scan and subsequent studies identified nine mutations in DCTN1, the largest protein subunit of the dynactin complex, in patients with Perry syndrome. These included G71A in the microtubule-binding cytoskeleton-associated protein Gly-rich domain of p150Glued. The dynactin complex is essential for function of the microtubule-based cytoplasmic retrograde motor dynein...
December 19, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29243911/neurodegenerative-disease-proteinopathies-are-connected-to-distinct-histone-post-translational-modification-landscapes
#13
Karen Chen, Seth A Bennett, Navin Rana, Huda Yousuf, Mohamed Said, Sadiqa Taaseen, Natalie Mendo, Steven Marc Meltser, Mariana Torrente
Amyotrophic Lateral Sclerosis (ALS) and Parkinson's disease (PD) are devastating neurodegenerative diseases involving the progressive degeneration of neurons. No cure is available for patients diagnosed with these diseases. A prominent feature for both ALS and PD is the accumulation of protein inclusions in the cytoplasm of degenerating neurons; however, the particular protein comprising these inclusions varies. The RNA-binding proteins TDP-43 and FUS are most notable in ALS, while α-synuclein aggregates into Lewy bodies in PD...
December 15, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29233983/endocytosis-regulates-tdp-43-toxicity-and-turnover
#14
Guangbo Liu, Alyssa N Coyne, Fen Pei, Spencer Vaughan, Matthew Chaung, Daniela C Zarnescu, J Ross Buchan
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. ALS-affected motor neurons exhibit aberrant localization of a nuclear RNA binding protein, TDP-43, into cytoplasmic aggregates, which contributes to pathology via unclear mechanisms. Here, we demonstrate that TDP-43 turnover and toxicity depend in part upon the endocytosis pathway. TDP-43 inhibits endocytosis, and co-localizes strongly with endocytic proteins, including in ALS patient tissue. Impairing endocytosis increases TDP-43 toxicity, aggregation, and protein levels, whereas enhancing endocytosis reverses these phenotypes...
December 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/29230997/-research-progress-of-the-relationship-between-the-expression-of-tar-dna-binding-domain-protein-43-and-brain-injury
#15
REVIEW
Y Ye, R B Li, S Y Ma, X T Wei, Q Xu
TAR DNA-binding domain protein 43 (TDP-43) is a highly conserved and widely expressed nuclear protein. Nowadays, the expression of TDP-43 can be found in most neurodegenerative diseases such as Alzheimer's disease, which makes it become a neurodegenerative disease associated marker protein. From the current research status at homeland and abroad, and around the relationship between the expression of TDP-43 and brain injury, this article emphatically probes into the specific expression and function of TDP-43 in acute and chronic brain injury based on the knowledge of its biological characteristics, which aims to explore the feasibility for determining the cause of death and the injury and disability situations by TDP-43 in forensic pathology...
June 2017: Fa Yi Xue za Zhi
https://www.readbyqxmd.com/read/29228211/asymmetry-of-post-mortem-neuropathology-in-behavioural-variant-frontotemporal-dementia
#16
David J Irwin, Corey T McMillan, Sharon X Xie, Katya Rascovsky, Vivianna M Van Deerlin, H Branch Coslett, Roy Hamilton, Geoffrey Aguirre, Edward B Lee, Virginia M Y Lee, John Q Trojanowski, Murray Grossman
Antemortem behavioural and anatomic abnormalities have largely been associated with right hemisphere disease in behavioural-variant frontotemporal dementia, but post-mortem neuropathological examination of bilateral hemispheres remains to be defined. Here we measured the severity of post-mortem pathology in both grey and white matter using a validated digital image analysis method in four cortical regions sampled from each hemisphere in 26 patients with behavioural-variant frontotemporal dementia, including those with frontotemporal degeneration (i...
December 8, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29216908/clinical-and-neuropathological-features-of-als-ftd-with-tia1-mutations
#17
Veronica Hirsch-Reinshagen, Cyril Pottier, Alexandra M Nicholson, Matt Baker, Ging-Yuek R Hsiung, Charles Krieger, Pheth Sengdy, Kevin B Boylan, Dennis W Dickson, Marsel Mesulam, Sandra Weintraub, Eileen Bigio, Lorne Zinman, Julia Keith, Ekaterina Rogaeva, Sasha A Zivkovic, David Lacomis, J Paul Taylor, Rosa Rademakers, Ian R A Mackenzie
Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases with TIA1 mutations, together with comparisons to sporadic ALS (sALS) and ALS due to repeat expansions in C9orf72 (C9orf72+). All nine patients with confirmed mutations in TIA1 were female. The clinical phenotype was heterogeneous with a range in the age at onset from late twenties to the eighth decade (mean = 60 years) and disease duration from one to 6 years (mean = 3 years)...
December 7, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29215728/multiple-neuronal-pathologies-are-common-in-young-patients-with-pathologically-proven-frontotemporal-lobar-degeneration
#18
Rachel H Tan, Yue Yang, Glenda M Halliday
AIMS: The past decade has seen a surge in studies identifying mixed pathologies in elderly populations. Importantly however, few studies have focussed on mixed pathology in Frontotemporal Lobar Degeneration (FTLD), particularly in younger cases. METHODS: The present study study examined concomitant pathological neuronal inclusions of TDP-43, hyperphosphorylated tau and α-synuclein protein in the anterior cingulate, hippocampus and entorhinal cortex in young (≤65 years at death) versus elderly (≥80 years at death) cases with pathologically-confirmed FTLD (n=52) or Alzheimer's disease (AD) (n=47)...
December 7, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/29213521/distinct-phospho-tdp-43-brain-distribution-in-two-cases-of-ftd-one-associated-with-als
#19
Álvaro C B Guedes, Ricardo Santin, André S R Costa, Keli C Reiter, Arlete Hilbig, Liana L Fernandez
INTRODUCTION: TDP-43 is an intranuclear protein involved in many cellular processes. When altered, it shows a change in pattern of distribution, as well as in functioning, throughout the Central Nervous System structures. Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS) are examples of TDP-43 proteinopathy. These disorders form a clinical spectrum, with some patients having a pure cognitive disorder while others also exhibit motor features. METHODS: We studied two donated brains from patients with a diagnosis of Frontotemporal Dementia (FTD), one of which was associated with ALS (ALS-FTD)...
July 2017: Dementia & Neuropsychologia
https://www.readbyqxmd.com/read/29213490/neuropathological-findings-in-entorhinal-cortex-of-subjects-aged-50-years-or-older-and-their-correlation-with-dementia-in-a-sample-from-southern-brazil
#20
Edson Rodrigues Neto, Mariana K Fonseca, Álvaro C B Guedes, Francine H Oliveira, Arlete Hilbig, Liana Lisboa Fernandez
Introduction: The aims of this study were to survey neurodegenerative changes detected by abnormal protein deposits in the Entorhinal Cortex (EC) of subjects aged 50 years or older and to correlate these findings with suspected dementia, as detected by the IQCODE (Informant Questionnaire on Cognitive Decline in the Elderly). Methods: Fourteen brains were submitted to the immunohistochemistry technique for different proteins (beta-amyloid, tau, α-synuclein and phospho-TDP-43) and data obtained compared with IQCODE scores...
January 2017: Dementia & Neuropsychologia
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