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https://www.readbyqxmd.com/read/29786080/atomic-structures-of-tdp-43-lcd-segments-and-insights-into-reversible-or-pathogenic-aggregation
#1
Elizabeth L Guenther, Qin Cao, Hamilton Trinh, Jiahui Lu, Michael R Sawaya, Duilio Cascio, David R Boyer, Jose A Rodriguez, Michael P Hughes, David S Eisenberg
The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules...
May 21, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29780824/clinical-histological-and-immunohistochemical-findings-in-inclusion-body-myositis
#2
Leonardo Valente de Camargo, Mary Souza de Carvalho, Samuel Katsuyuki Shinjo, Acary Souza Bulle de Oliveira, Edmar Zanoteli
Sporadic inclusion body myositis (sIBM) is considered the most common acquired myopathy aged over 50 years. The disease is characterized by a particular process of muscle degeneration characterized by abnormal deposit of protein aggregates in association with inflammation. The aim of this study was to present clinical and muscle histopathological findings, including immunostaining for LC3B, p62, α -synuclein, and TDP-43, in 18 patients with sIBM. The disease predominated in males (61%) and European descendants, with onset of clinical manifestations around 59 years old...
2018: BioMed Research International
https://www.readbyqxmd.com/read/29779213/differential-toxicity-of-tdp-43-isoforms-depends-on-their-sub-mitochondrial-localization-in-neuronal-cells
#3
Illari Salvatori, Alberto Ferri, Silvia Scaricamazza, Ilaria Giovannelli, Alessia Serrano, Simona Rossi, Nadia D'Ambrosi, Mauro Cozzolino, Andrea Di Giulio, Sandra Moreno, Cristiana Valle, Maria Teresa Carrì
TAR DNA binding protein 43 (TDP-43) is an RNA binding protein and a major component of protein aggregates found in Amyotrophic Lateral Sclerosis and several other neurodegenerative diseases. TDP-43 exists as a full length protein and as two shorter forms of 25 and 35 kDa. Full length mutant TDP-43s found in ALS patients re-localize from the nucleus to the cytoplasm and in part to mitochondria, where they exert a toxic role associated with neurodegeneration. However, induction of mitochondrial damage by TDP-43 fragments is yet to be clarified...
May 20, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29778779/ftld-als-linked-tdp-43-mutations-do-not-alter-tdp-43-s-ability-to-self-regulate-its-expression-in-drosophila
#4
Laetitia Miguel, Tracey Avequin, Marine Pons, Thierry Frébourg, Dominique Campion, Magalie Lecourtois
TDP-43 is a major disease-causing protein in amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). Today, more than 50 missense mutations in the TARDBP/TDP-43 gene have been described in patients with FTLD/ALS. However, the functional consequences of FTLD/ALS-linked TDP-43 mutations are not fully elucidated. In the physiological state, TDP-43 expression is tightly regulated through an autoregulatory negative feedback loop. Maintaining normal TDP-43 protein levels is critical for proper physiological functions of the cells...
May 17, 2018: Brain Research
https://www.readbyqxmd.com/read/29777184/genotype-phenotype-links-in-frontotemporal-lobar-degeneration
#5
REVIEW
Sara Van Mossevelde, Sebastiaan Engelborghs, Julie van der Zee, Christine Van Broeckhoven
Frontotemporal lobar degeneration (FTLD) represents a group of neurodegenerative brain diseases with highly heterogeneous clinical, neuropathological and genetic characteristics. This high degree of heterogeneity results from the presence of several different underlying molecular disease processes; consequently, it is unlikely that all patients with FTLD will benefit from a single therapy. Therapeutic strategies for FTLD are currently being explored, and tools are urgently needed that enable the selection of patients who are the most likely to benefit from a particular therapy...
May 18, 2018: Nature Reviews. Neurology
https://www.readbyqxmd.com/read/29769403/unmasking-the-skiptic-task-of-tdp-43
#6
Caroline Rouaux, Jose-Luis Gonzalez De Aguilar, Luc Dupuis
No abstract text is available yet for this article.
May 16, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29765078/tdp-43-regulation-of-stress-granule-dynamics-in-neurodegenerative-disease-relevant-cell-types
#7
Yousra Khalfallah, Rachel Kuta, Camille Grasmuck, Alexandre Prat, Heather D Durham, Christine Vande Velde
Stress granules (SGs) are cytoplasmic foci that form in response to various external stimuli and are essential to cell survival following stress. SGs are studied in several diseases, including ALS and FTD, which involve the degeneration of motor and cortical neurons, respectively, and are now realized to be linked pathogenically by TDP-43, originally discovered as a component of ubiquitin-positive aggregates within patients' neurons and some glial cells. So far, studies to undercover the role of TDP-43 in SGs have used primarily transformed cell lines, and thus rely on the extrapolation of the mechanisms to cell types affected in ALS/FTD, potentially masking cell specific effects...
May 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29764981/mice-with-endogenous-tdp-43-mutations-exhibit-gain-of-splicing-function-and-characteristics-of-amyotrophic-lateral-sclerosis
#8
Pietro Fratta, Prasanth Sivakumar, Jack Humphrey, Kitty Lo, Thomas Ricketts, Hugo Oliveira, Jose M Brito-Armas, Bernadett Kalmar, Agnieszka Ule, Yichao Yu, Nicol Birsa, Cristian Bodo, Toby Collins, Alexander E Conicella, Alan Mejia Maza, Alessandro Marrero-Gagliardi, Michelle Stewart, Joffrey Mianne, Silvia Corrochano, Warren Emmett, Gemma Codner, Michael Groves, Ryutaro Fukumura, Yoichi Gondo, Mark Lythgoe, Erwin Pauws, Emma Peskett, Philip Stanier, Lydia Teboul, Martina Hallegger, Andrea Calvo, Adriano Chiò, Adrian M Isaacs, Nicolas L Fawzi, Eric Wang, David E Housman, Francisco Baralle, Linda Greensmith, Emanuele Buratti, Vincent Plagnol, Elizabeth Mc Fisher, Abraham Acevedo-Arozena
TDP-43 (encoded by the gene TARDBP ) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP-43 function at physiological levels both in vitro and in vivo Interestingly, we find that mutations within the C-terminal domain of TDP-43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP-43 loss- and gain-of-function effects...
May 15, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29760282/the-c-elegans-ortholog-of-tdp-43-regulates-the-chromatin-localization-of-the-heterochromatin-protein-1-homolog-hpl-2
#9
Tassa K Saldi, Patrick Gonzales, Alfonso Garrido-Lecca, Vishantie Dostal, Christine M Roberts, Leonard Petrucelli, Christopher D Link
TDP-1 is the C. elegans ortholog of mammalian TDP-43, which is strongly implicated in the etiology of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). We discovered that deletion of the tdp-1 gene results in enhanced nuclear RNA interference (RNAi). As nuclear RNAi in C. elegans involves chromatin changes moderated by HPL-2, a homolog of heterochromatin protein 1 (HP1), we investigated the interaction of TDP-1 and HPL-2. We find that TDP-1 and HPL-2 interact directly, and loss of TDP-1 dramatically alters the chromatin association of HPL-2...
May 14, 2018: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29755516/synaptic-paths-to-neurodegeneration-the-emerging-role-of-tdp-43-and-fus-in-synaptic-functions
#10
REVIEW
Shuo-Chien Ling
TAR DNA-binding protein-43 KDa (TDP-43) and fused in sarcoma (FUS) as the defining pathological hallmarks for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coupled with ALS-FTD-causing mutations in both genes, indicate that their dysfunctions damage the motor system and cognition. On the molecular level, TDP-43 and FUS participate in the biogenesis and metabolism of coding and noncoding RNAs as well as in the transport and translation of mRNAs as part of cytoplasmic mRNA-ribonucleoprotein (mRNP) granules...
2018: Neural Plasticity
https://www.readbyqxmd.com/read/29752072/tar-dna-binding-protein-43-and-disrupted-in-schizophrenia-1-coaggregation-disrupts-dendritic-local-translation-and-mental-function-in-frontotemporal-lobar-degeneration
#11
Ryo Endo, Noriko Takashima, Yoko Nekooki-Machida, Yusuke Komi, Kelvin Kai-Wan Hui, Masaki Takao, Hiroyasu Akatsu, Shigeo Murayama, Akira Sawa, Motomasa Tanaka
BACKGROUND: Neurodegenerative diseases involving protein aggregation often accompany psychiatric symptoms. Frontotemporal lobar degeneration (FTLD) associated with TAR DNA-binding protein 43 (TDP-43) aggregation is characterized by progressive neuronal atrophy in frontal and temporal lobes of cerebral cortex. Furthermore, patients with FTLD display mental dysfunction in multiple behavioral dimensions. Nevertheless, their molecular origin for psychiatric symptoms remains unclear. METHODS: In FTLD neurons and mouse models with TDP-43 aggregates, we examined coaggregation between TDP-43 and disrupted in schizophrenia 1 (DISC1), a key player in the pathology of mental conditions and its effects on local translation in dendrites and psychiatric behaviors...
March 29, 2018: Biological Psychiatry
https://www.readbyqxmd.com/read/29751289/perfusion-alterations-converge-with-patterns-of-pathological-spread-in-transactive-response-dna-binding-protein-43-proteinopathies
#12
Pilar M Ferraro, Charles Jester, Christopher A Olm, Katerina Placek, Federica Agosta, Lauren Elman, Leo McCluskey, David J Irwin, John A Detre, Massimo Filippi, Murray Grossman, Corey T McMillan
Amyotrophic lateral sclerosis (ALS) and the behavioral variant of frontotemporal dementia (bvFTD) commonly share the presence of transactive response DNA-binding protein 43 (TDP-43) inclusions. Structural magnetic resonance imaging studies demonstrated evidence for TDP-43 pathology spread, but while structural imaging usually reveals overt neuronal loss, perfusion imaging may detect more subtle neural activity alterations. We evaluated perfusion as an early marker for incipient pathology-associated brain alterations in TDP-43 proteinopathies...
April 17, 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29751083/the-amyloidogenicity-of-a-c-terminal-region-of-tdp-43-implicated-in-amyotrophic-lateral-sclerosis-can-be-affected-by-anions-acetylation-and-homodimerization
#13
Archana Prasad, Vishwanath Sivalingam, Vidhya Bharathi, Amandeep Girdhar, Basant K Patel
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease associated with accumulation of hyper-phosphorylated, and ubiquitinated TAR DNA-binding protein-43 (TDP-43) as inclusion deposits in neuronal cells. Recently, amyloid-like fibrillar aggregates of TDP-43 have been reported from several ALS patients. The C-terminal region of TDP-43 is central to TDP-43's pathological aggregation and most of the familial ALS mutations in the encoding TARDBP gene are located in this domain. Also, aberrant proteolytic cleavages of TDP-43 produce cytotoxic C-terminal fragments of ∼15-35 kDa...
May 8, 2018: Biochimie
https://www.readbyqxmd.com/read/29750243/c9orf72-dipeptide-repeat-poly-ga-inclusions-promote-intracellular-aggregation-of-phosphorylated-tdp-43
#14
Takashi Nonaka, Masami Masuda-Suzukake, Masato Hosokawa, Aki Shimozawa, Shinobu Hirai, Haruo Okado, Masato Hasegawa
Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are neurodegenerative diseases characterized by accumulation of insoluble aggregates of phosphorylated 43-kDa TAR DNA-binding protein (TDP-43), and linked with abnormal expansion of a hexanucleotide repeat in an intron of chromosome 9 open reading frame 72 (C9ORF72). However, the relationship between C9ORF72 mutations and TDP-43 aggregation remains unknown. Non-ATG-dependent translation of C9ORF72 repeats produces dipeptide repeat (DPR) proteins, which form p62-positive aggregates in cerebral cortex and cerebellum of patients...
May 10, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29742622/fluorescence-in-situ-hybridization-method-reveals-that-carboxyl-terminal-fragments-of-transactive-response-dna-binding-protein-43-truncated-at-the-amino-acid-residue-218-reduce-poly-a-rna-expression
#15
Shinji Higashi, Ryohei Watanabe, Tetsuaki Arai
Transactive response (TAR) DNA-binding protein 43 (TDP-43) has emerged as an important contributor to amyotrophic lateral sclerosis and frontotemporal lobar degeneration. To understand the association of TDP-43 with complex RNA processing in disease pathogenesis, we performed fluorescence in-situ hybridization using HeLa cells transfected with a series of deleted TDP-43 constructs and investigated the effect of truncation of TDP-43 on the expression of poly(A) RNA. Endogenous and overexpressed full-length TDP-43 localized to the perichromatin region and interchromatin space adjacent to poly(A) RNA...
May 8, 2018: Neuroreport
https://www.readbyqxmd.com/read/29737853/correction-to-rna-and-protein-interactors-with-tdp-43-in-human-spinal-cord-lysates-in-amyotrophic-lateral-sclerosis
#16
Kathryn Volkening, Brian A Keller, Cheryl Leystra-Lantz, Michael J Strong
No abstract text is available yet for this article.
May 8, 2018: Journal of Proteome Research
https://www.readbyqxmd.com/read/29734651/acetylation-disfavors-tau-phase-separation
#17
Josephine C Ferreon, Antrix Jain, Kyoung-Jae Choi, Phoebe S Tsoi, Kevin R MacKenzie, Sung Yun Jung, Allan Chris Ferreon
Neuropathological aggregates of the intrinsically disordered microtubule-associated protein Tau are hallmarks of Alzheimer’s disease, with decades of research devoted to studying the protein’s aggregation properties both in vitro and in vivo. Recent demonstrations that Tau is capable of undergoing liquid-liquid phase separation (LLPS) reveal the possibility that protein-enriched phase separated compartments could serve as initiation sites for Tau aggregation, as shown for other amyloidogenic proteins, such as the Fused in Sarcoma protein (FUS) and TAR DNA-binding protein-43 (TDP-43)...
May 4, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29731706/phosphorylation-of-threonine-175-tau-in-the-induction-of-tau-pathology-in-amyotrophic-lateral-sclerosis-frontotemporal-spectrum-disorder-als-ftsd-a-review
#18
REVIEW
Alexander J Moszczynski, Matthew A Hintermayer, Michael J Strong
Approximately 50-60% of all patients with amyotrophic lateral sclerosis (ALS) will develop a deficit of frontotemporal function, ranging from frontotemporal dementia (FTD) to one or more deficits of neuropsychological, speech or language function which are collectively known as the frontotemporal spectrum disorders of ALS (ALS-FTSD). While the neuropathology underlying these disorders is most consistent with a widespread alteration in the metabolism of transactive response DNA-binding protein 43 (TDP-43), in both ALS with cognitive impairment (ALSci) and ALS with FTD (ALS-FTD; also known as MND-FTD) there is evidence for alterations in the metabolism of the microtubule associated protein tau...
2018: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/29728608/active-nuclear-import-and-passive-nuclear-export-are-the-primary-determinants-of-tdp-43-localization
#19
Emile S Pinarbasi, Tolga Cağatay, Ho Yee Joyce Fung, Ying C Li, Yuh Min Chook, Philip J Thomas
ALS (Amyotrophic Lateral Sclerosis) is a neurodegenerative disease characterized by the redistribution of the RNA binding protein TDP-43 in affected neurons: from predominantly nuclear to aggregated in the cytosol. However, the determinants of TDP-43 localization and the cellular insults that promote redistribution are incompletely understood. Here, we show that the putative Nuclear Export Signal (NES) is not required for nuclear egress of TDP-43. Moreover, when the TDP-43 domain which contains the putative NES is fused to a reporter protein, YFP, the presence of the NES is not sufficient to mediate nuclear exclusion of the fusion protein...
May 4, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29728564/nuclear-egress-of-tdp-43-and-fus-occurs-independently-of-exportin-1-crm1
#20
Helena Ederle, Christina Funk, Claudia Abou-Ajram, Saskia Hutten, Eva B E Funk, Ralph H Kehlenbach, Susanne M Bailer, Dorothee Dormann
TDP-43 and FUS are nuclear proteins with multiple functions in mRNA processing. They play key roles in ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia), where they are partially lost from the nucleus and aggregate in the cytoplasm of neurons and glial cells. Defects in nucleocytoplasmic transport contribute to this pathology, hence nuclear import of both proteins has been studied in detail. However, their nuclear export routes remain poorly characterized and it is unclear whether aberrant nuclear export contributes to TDP-43 or FUS pathology...
May 4, 2018: Scientific Reports
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