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TDP-43

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https://www.readbyqxmd.com/read/28432364/rrm-domain-of-als-ftd-causing-fus-characteristic-of-irreversible-unfolding-spontaneously-self-assembles-into-amyloid-fibrils
#1
Yimei Lu, Liangzhong Lim, Jianxing Song
526-residue FUS functions to self-assemble into reversible droplets/hydrogels, which could be further solidified into pathological fibrils. FUS is intrinsically prone to aggregation, composed of N-terminal low-sequence complexity (LC); RNA-recognition motif (RRM) and C-terminal LC domains. Intriguingly, previous in vivo studies revealed that its RRM is required for manifesting FUS cytotoxicity but the underlying mechanism remains unknown. Here, we characterized solution conformations of FUS and its five differentially dissected fragments, followed by detailed investigations on thermal unfolding, NMR dynamics and self-assembly of RRM...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28431575/heterogeneous-ribonuclear-protein-a3-hnrnp-a3-is-present-in-dipeptide-repeat-protein-containing-inclusions-in-frontotemporal-lobar-degeneration-and-motor-neurone-disease-associated-with-expansions-in-c9orf72-gene
#2
Yvonne S Davidson, Louis Flood, Andrew C Robinson, Yoshihiro Nihei, Kohji Mori, Sara Rollinson, Anna Richardson, Bridget C Benson, Matthew Jones, Julie S Snowden, Stuart Pickering-Brown, Christian Haass, Tammaryn Lashley, David M A Mann
Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter behaviour, personality and language. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP A1, A2/B1 and A3 was performed on sections of temporal cortex with hippocampus from 61 patients with FTLD, stratified by pathological hallmarks into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those without known mutation...
April 21, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28421535/microrna-metabolism-and-dysregulation-in-amyotrophic-lateral-sclerosis
#3
REVIEW
Paola Rinchetti, Mafalda Rizzuti, Irene Faravelli, Stefania Corti
MicroRNAs (miRNAs) are a subset of endogenous, small, non-coding RNA molecules involved in the post-transcriptional regulation of eukaryotic gene expression. Dysregulation in miRNA-related pathways in the central nervous system (CNS) is associated with severe neuronal injury and cell death, which can lead to the development of neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). ALS is a fatal adult onset disease characterized by the selective loss of upper and lower motor neurons. While the pathogenesis of ALS is still largely unknown, familial ALS forms linked to TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS) gene mutations, as well as sporadic forms, display changes in several steps of RNA metabolism, including miRNA processing...
April 18, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28416393/tdp-43-expression-influences-amyloid%C3%AE-plaque-deposition-and-tau-aggregation
#4
Stephani A Davis, Kok Ann Gan, James A Dowell, Nigel J Cairns, Michael A Gitcho
Although the main focus in Alzheimer's disease (AD) has been an investigation of mechanisms causing Aβ plaque deposition and tau tangle formation, recent studies have shown that phosphorylated TDP-43 pathology is present in up to 50% of sporadic cases. Furthermore, elevated phosphorylated TDP-43 has been associated with more severe AD pathology. Therefore, we hypothesized that TDP-43 may regulate amyloid-beta precursor protein (APP) trafficking and tau phosphorylation/aggregation. In order to examine the role of TDP-43 in AD, we developed a transgenic mouse that overexpresses hippocampal and cortical neuronal TDP-43 in a mouse expressing familial mutations (K595N and M596L) in APP and presenilin 1 (PSEN1ΔE9)...
April 14, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28409281/spinal-poly-ga-inclusions-in-a-c9orf72-mouse-model-trigger-motor-deficits-and-inflammation-without-neuron-loss
#5
Martin H Schludi, Lore Becker, Lillian Garrett, Tania F Gendron, Qihui Zhou, Franziska Schreiber, Bastian Popper, Leda Dimou, Tim M Strom, Juliane Winkelmann, Anne von Thaden, Kristin Rentzsch, Stephanie May, Meike Michaelsen, Benjamin M Schwenk, Jing Tan, Benedikt Schoser, Marianne Dieterich, Leonard Petrucelli, Sabine M Hölter, Wolfgang Wurst, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Thomas Klopstock, Thomas Arzberger, Dieter Edbauer
Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples...
April 13, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28405022/therapeutic-reduction-of-ataxin-2-extends-lifespan-and-reduces-pathology-in-tdp-43-mice
#6
Lindsay A Becker, Brenda Huang, Gregor Bieri, Rosanna Ma, David A Knowles, Paymaan Jafar-Nejad, James Messing, Hong Joo Kim, Armand Soriano, Georg Auburger, Stefan M Pulst, J Paul Taylor, Frank Rigo, Aaron D Gitler
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that is characterized by motor neuron loss and that leads to paralysis and death 2-5 years after disease onset. Nearly all patients with ALS have aggregates of the RNA-binding protein TDP-43 in their brains and spinal cords, and rare mutations in the gene encoding TDP-43 can cause ALS. There are no effective TDP-43-directed therapies for ALS or related TDP-43 proteinopathies, such as frontotemporal dementia. Antisense oligonucleotides (ASOs) and RNA-interference approaches are emerging as attractive therapeutic strategies in neurological diseases...
April 20, 2017: Nature
https://www.readbyqxmd.com/read/28402699/inhibition-of-retrograde-transport-modulates-misfolded-protein-accumulation-and-clearance-in-motoneuron-diseases
#7
Riccardo Cristofani, Valeria Crippa, Paola Rusmini, Maria Elena Cicardi, Marco Meroni, Nausicaa V Licata, Gessica Sala, Elisa Giorgetti, Christopher Grunseich, Mariarita Galbiati, Margherita Piccolella, Elio Messi, Carlo Ferrarese, Serena Carra, Angelo Poletti
Motoneuron diseases, like spinal bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS), are associated with proteins that because of gene mutation or peculiar structures, acquire aberrant (misfolded) conformations toxic to cells. To prevent misfolded protein toxicity, cells activate a protein quality control (PQC) system composed of chaperones and degradative pathways (proteasome and autophagy). Inefficient activation of the PQC system results in misfolded protein accumulation that ultimately leads to neuronal cell death, while efficient macroautophagy/autophagy-mediated degradation of aggregating proteins is beneficial...
April 12, 2017: Autophagy
https://www.readbyqxmd.com/read/28401333/interactions-of-pathological-proteins-in-neurodegenerative-diseases
#8
REVIEW
Tara L Spires-Jones, Johannes Attems, Dietmar Rudolf Thal
Neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal lobar degeneration (FTD), Lewy body disease (LBD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) have in common that protein aggregates represent pathological hallmark lesions. Amyloid β-protein, τ-protein, α-synuclein, and TDP-43 are the most frequently aggregated proteins in these disorders. Although they are assumed to form disease-characteristic aggregates, such as amyloid plaques and neurofibrillary tangles in AD or Lewy bodies in LBD/PD, they are not restricted to these clinical presentations...
April 11, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28396410/spinal-motor-neuron-protein-supersaturation-patterns-are-associated-with-inclusion-body-formation-in-als
#9
Prajwal Ciryam, Isabella A Lambert-Smith, Daniel M Bean, Rosie Freer, Fernando Cid, Gian Gaetano Tartaglia, Darren N Saunders, Mark R Wilson, Stephen G Oliver, Richard I Morimoto, Christopher M Dobson, Michele Vendruscolo, Giorgio Favrin, Justin J Yerbury
Amyotrophic lateral sclerosis (ALS) is a heterogeneous degenerative motor neuron disease linked to numerous genetic mutations in apparently unrelated proteins. These proteins, including SOD1, TDP-43, and FUS, are highly aggregation-prone and form a variety of intracellular inclusion bodies that are characteristic of different neuropathological subtypes of the disease. Contained within these inclusions are a variety of proteins that do not share obvious characteristics other than coaggregation. However, recent evidence from other neurodegenerative disorders suggests that disease-affected biochemical pathways can be characterized by the presence of proteins that are supersaturated, with cellular concentrations significantly greater than their solubilities...
April 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28395086/regional-overlap-of-pathologies-in-lewy-body-disorders
#10
Martí Colom-Cadena, Oriol Grau-Rivera, Lluís Planellas, Catalina Cerquera, Estrella Morenas, Sergio Helgueta, Laia Muñoz, Jaime Kulisevsky, Maria Jose Martí, Eduard Tolosa, Jordi Clarimon, Alberto Lleó, Ellen Gelpi
Lewy body disorders (LBD) are common neurodegenerative diseases characterized by the presence of aggregated α-synuclein in Lewy bodies and Lewy neurites in the central and peripheral nervous systems. The brains of patients with LBD often display other comorbid pathologies, i.e. insoluble tau, β-amyloid aggregates, TAR DNA-binding protein 43 (TDP-43) deposits, and argyrophilic grain disease (AGD). The incidence and physiological relevance of these concurrent pathological findings remain controversial. We performed a semiquantitative detailed mapping of α-synuclein, tau, β-amyloid (Aβ), TDP-43, and AGD pathologies in 17 areas in 63 LBD cases (44 with Parkinson disease [PD], 28 with dementia, and 19 with dementia with Lewy bodies)...
March 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28389532/rna-binding-proteins-with-prion-like-domains-in-health-and-disease
#11
REVIEW
Alice Ford Harrison, James Shorter
Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid-liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease...
April 7, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28384473/sca31-flies-perform-in-a-balancing-act-between-ran-translation-and-rna-binding-proteins
#12
George R Jackson
In this issue of Neuron, Ishiguro et al. (2017) explore the toxicity of RAN translation in spinocerebellar ataxia 31. Using a Drosophila model, the authors demonstrate that TDP-43 and other RNA-binding proteins act as chaperones to regulate the formation of toxic RNA aggregates.
April 5, 2017: Neuron
https://www.readbyqxmd.com/read/28380257/tdp-43-and-fus-en-route-from-the-nucleus-to-the-cytoplasm
#13
REVIEW
Helena Ederle, Dorothee Dormann
Misfolded or mislocalized RNA-binding proteins (RBPs) and, consequently, altered mRNA processing, can cause neuronal dysfunction, eventually leading to neurodegeneration. Two prominent examples are the RBPs TDP-43 (TAR DNA binding protein of 43 kDa) and FUS (Fused in sarcoma), which form pathological mRNP aggregates in patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative disorders. Here, we review the multiple functions of TDP-43 and FUS in mRNA processing, both in the nucleus and in the cytoplasm...
April 5, 2017: FEBS Letters
https://www.readbyqxmd.com/read/28379416/absence-of-alzheimer-disease-neuropathologic-changes-in-eyes-of-subjects-with-alzheimer-disease
#14
Erik A Williams, Declan McGuone, Matthew P Frosch, Bradley T Hyman, Nora Laver, Anat Stemmer-Rachamimov
Alzheimer disease (AD) is the most common cause of dementia in the elderly, and is characterized by extracellular deposition of β-amyloid and intracellular accumulation of hyperphosphorylated tau protein in the brain. These pathologic findings are identified postmortem. Various visual deficits in AD have been reported and there have been conflicting reports, through imaging and pathology studies, regarding the presence of changes in the globe that mirror Alzheimer changes in the brain. Moreover, both macular degeneration and glaucoma have been variously characterized as having AD-related features...
March 30, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28373710/single-cell-imaging-and-quantification-of-tdp-43-and-%C3%AE-synuclein-intercellular-propagation
#15
Sivan Peled, Dorin Sade, Yaron Bram, Ziv Porat, Topaz Kreiser, Michael Mimouni, Alexandra Lichtenstein, Daniel Segal, Ehud Gazit
The intercellular spreading of protein assemblies is a major factor in the progression of neurodegenerative disorders. The quantitative study and visualization of cell-to-cell propagation using tagged-proteins is challenging due to the steric effect of relatively large fluorescence tags and the risk of 'false positive' identification when analyzing these rare transmission events. Here, we established a cell culture model to characterize the cell-to-cell transmission of TAR DNA-binding protein and α-synuclein, involved in amyotrophic lateral sclerosis and Parkinson's disease, respectively, using the small nine amino acid influenza hemagglutinin tag...
March 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28372328/blood-based-oligomeric-and-other-protein-variant-biomarkers-to-facilitate-pre-symptomatic-diagnosis-and-staging-of-alzheimer-s-disease
#16
Stephanie M Williams, Philip Schulz, Terrone L Rosenberry, Richard J Caselli, Michael R Sierks
Oligomeric forms of amyloid-β (Aβ), tau, and TDP-43 play important roles in Alzheimer's disease (AD), and therefore are promising biomarkers. We previously generated single chain antibody fragments (scFvs) that selectively bind disease-related variants of these proteins including A4, C6T, and E1, which bind different oligomeric Aβ variants; D11C, which binds oligomeric tau; and AD-TDP1 and AD-TDP2, which bind disease related TDP-43 variants. To determine the utility of these disease-related variants as early biomarkers, we first analyzed 11 human sera samples obtained ∼2 years prior to an initial mild cognitive impairment (MCI) diagnosis...
March 29, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28367944/-original-article-tdp-43-in-the-skin-of-amyotrophic-lateral-sclerosis-patients
#17
Keisuke Abe, Takuya Ohkubo, Takanori Yokota
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. A common characteristic of ALS pathology is cytoplasmic inclusions primarily composed of transactive response DNA-binding protein of 43 kDa (TDP-43). Production of TDP-43 in the central nervous system is strictly regulated, but it is not known whether this is also true in the skin of ALS patients. We found a gradual but significant reduction in epidermal TDP-43 mRNA expression with illness progression in ALS patients with upper-limb onset...
2017: Journal of Medical and Dental Sciences
https://www.readbyqxmd.com/read/28358904/neurotrophic-effects-of-progranulin-in-vivo-in-reversing-motor-neuron-defects-caused-by-over-or-under-expression-of-tdp-43-or-fus
#18
Babykumari P Chitramuthu, Denis G Kay, Andrew Bateman, Hugh P J Bennett
Progranulin (PGRN) is a glycoprotein with multiple roles in normal and disease states. Mutations within the GRN gene cause frontotemporal lobar degeneration (FTLD). The affected neurons display distinctive TAR DNA binding protein 43 (TDP-43) inclusions. How partial loss of PGRN causes TDP-43 neuropathology is poorly understood. TDP-43 inclusions are also found in affected neurons of patients with other neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. In ALS, TDP-43 inclusions are typically also immunoreactive for fused in sarcoma (FUS)...
2017: PloS One
https://www.readbyqxmd.com/read/28357566/mutant-tdp-43-within-motor-neurons-drives-disease-onset-but-not-progression-in-amyotrophic-lateral-sclerosis
#19
Dara Ditsworth, Marcus Maldonado, Melissa McAlonis-Downes, Shuying Sun, Amanda Seelman, Kevin Drenner, Eveline Arnold, Shuo-Chien Ling, Donald Pizzo, John Ravits, Don W Cleveland, Sandrine Da Cruz
Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43(Q331K) mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons...
March 29, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28344074/aberrant-distributions-of-nuclear-pore-complex-proteins-in-als-mice-and-als-patients
#20
Jingwei Shang, Toru Yamashita, Yumiko Nakano, Ryuta Morihara, Xianghong Li, Tian Feng, Xia Liu, Yong Huang, Yusuke Fukui, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe
Nuclear pore complexes (NPCs) play important roles in traffic of molecules between the nucleus and cytoplasm, aberrant distributions of components of NPCs were demonstrated in C9orf72 amyotrophic lateral sclerosis (C9-ALS) patients, but it is elusive whether such abnormities are also the case with other cause of ALS disease. In the present study, we investigated the spatiotemporal distributions of RanGAP1 and 4 representative nucleoporins (GP210, NUP205, NUP107 and NUP50) of NPCs in human Cu/Zn superoxide dismutase-1 mutation transgenic (SOD1-Tg) mice and sporadic ALS patients...
March 24, 2017: Neuroscience
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