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https://www.readbyqxmd.com/read/28637276/repetitive-element-transcripts-are-elevated-in-the-brain-of-c9orf72-als-ftld-patients
#1
Mercedes Prudencio, Patrick K Gonzales, Casey N Cook, Tania F Gendron, Lillian M Daughrity, Yuping Song, Mark T W Ebbert, Marka van Blitterswijk, Yong-Jie Zhang, Karen Jansen-West, Matthew C Baker, Michael DeTure, Rosa Rademakers, Kevin B Boylan, Dennis W Dickson, Leonard Petrucelli, Christopher D Link
Significant transcriptome alterations are detected in the brain of patients with amyotrophic lateral sclerosis (ALS), including carriers of the C9orf72 repeat expansion and C9orf72-negative sporadic cases. Recently, the expression of repetitive element transcripts has been associated with toxicity and, while increased repetitive element expression has been observed in several neurodegenerative diseases, little is known about their contribution to ALS. To assess whether aberrant expression of repetitive element sequences are observed in ALS, we analyzed RNA sequencing data from C9orf72-positive and sporadic ALS cases, as well as healthy controls...
June 16, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28633435/mcm3ap-in-recessive-charcot-marie-tooth-neuropathy-and-mild-intellectual-disability
#2
Emil Ylikallio, Rosa Woldegebriel, Manuela Tumiati, Pirjo Isohanni, Monique M Ryan, Zornitza Stark, Maie Walsh, Sarah L Sawyer, Katrina M Bell, Alicia Oshlack, Paul J Lockhart, Mariia Shcherbii, Alejandro Estrada-Cuzcano, Derek Atkinson, Taila Hartley, Martine Tetreault, Inge Cuppen, W Ludo van der Pol, Ayse Candayan, Esra Battaloglu, Yesim Parman, Koen L I van Gassen, Marie-José H van den Boogaard, Kym M Boycott, Liisa Kauppi, Albena Jordanova, Tuula Lönnqvist, Henna Tyynismaa
Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function...
June 19, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28625595/dctn1-related-neurodegeneration-perry-syndrome-and-beyond
#3
REVIEW
Takuya Konno, Owen A Ross, Hélio A G Teive, Jarosław Sławek, Dennis W Dickson, Zbigniew K Wszolek
Perry syndrome (PS) is a rare hereditary neurodegenerative disease characterized by autosomal dominant parkinsonism, psychiatric symptoms, weight loss, central hypoventilation, and distinct TDP-43 pathology. The mutated causative gene for PS is DCTN1, which encodes the dynactin subunit p150(Glued). Dynactin is a motor protein involved in axonal transport; the p150(Glued) subunit has a critical role in the overall function. Since the discovery of DCTN1 in PS, it has been increasingly recognized that DCTN1 mutations can exhibit more diverse phenotypes than previously thought...
June 12, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/28625517/reduced-tdp-43-expression-improves-neuronal-activities-in-a-drosophila-model-of-perry-syndrome
#4
Yuka Hosaka, Tsuyoshi Inoshita, Kahori Shiba-Fukushima, Changxu Cui, Taku Arano, Yuzuru Imai, Nobutaka Hattori
Parkinsonian Perry syndrome, involving mutations in the dynein motor component dynactin or p150(Glued), is characterized by TDP-43 pathology in affected brain regions, including the substantia nigra. However, the molecular relationship between p150(Glued) and TDP-43 is largely unknown. Here, we report that a reduction in TDP-43 protein levels alleviates the synaptic defects of neurons expressing the Perry mutant p150(G50R) in Drosophila. Dopaminergic expression of p150(G50R), which decreases dopamine release, disrupts motor ability and reduces the lifespan of Drosophila...
June 8, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28622300/the-als-linked-e102q-mutation-in-sigma-receptor-1-leads-to-er-stress-mediated-defects-in-protein-homeostasis-and-dysregulation-of-rna-binding-proteins
#5
Alice Dreser, Jan Tilmann Vollrath, Antonio Sechi, Sonja Johann, Andreas Roos, Alfred Yamoah, Istvan Katona, Saeed Bohlega, Dominik Wiemuth, Yuemin Tian, Axel Schmidt, Jörg Vervoorts, Marc Dohmen, Cordian Beyer, Jasper Anink, Eleonora Aronica, Dirk Troost, Joachim Weis, Anand Goswami
Amyotrophic lateral sclerosis (ALS) is characterized by the selective degeneration of motor neurons (MNs) and their target muscles. Misfolded proteins which often form intracellular aggregates are a pathological hallmark of ALS. Disruption of the functional interplay between protein degradation (ubiquitin proteasome system and autophagy) and RNA-binding protein homeostasis has recently been suggested as an integrated model that merges several ALS-associated proteins into a common pathophysiological pathway...
June 16, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28620838/modelling-fus-mislocalisation-in-an-in-vitro-model-of-innervated-human-muscle
#6
Sonja Prpar Mihevc, Mojca Pavlin, Simona Darovic, Marko Živin, Matej Podbregar, Boris Rogelj, Tomaz Mars
Degeneration of distal axons and neuromuscular junctions is an early feature in the pathology of amyotrophic lateral sclerosis (ALS), which culminates in motor neuron loss due to axon retraction and muscle atrophy. The complex interactions in the pathogenesis of ALS between motor neurons, muscle cells and accompanying glia require an appropriate experimental model. Here, we have defined a co-culture model based on human myotubes innervated by neurons from embryonic rat spinal cord explants to investigate the pathology and treatment of ALS...
June 15, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28611593/autophagy-and-its-impact-on-neurodegenerative-diseases-new-roles-for-tdp-43-and-c9orf72
#7
REVIEW
Mauricio Budini, Emanuele Buratti, Eugenia Morselli, Alfredo Criollo
Autophagy is a catabolic mechanism where intracellular material is degraded by vesicular structures called autophagolysosomes. Autophagy is necessary to maintain the normal function of the central nervous system (CNS), avoiding the accumulation of misfolded and aggregated proteins. Consistently, impaired autophagy has been associated with the pathogenesis of various neurodegenerative diseases. The proteins TAR DNA-binding protein-43 (TDP-43), which regulates RNA processing at different levels, and chromosome 9 open reading frame 72 (C9orf72), probably involved in membrane trafficking, are crucial in the development of neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD)...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28608264/the-small-heat-shock-protein-b8-hspb8-efficiently-removes-aggregating-species-of-dipeptides-produced-in-c9orf72-related-neurodegenerative-diseases
#8
Riccardo Cristofani, Valeria Crippa, Giulia Vezzoli, Paola Rusmini, Mariarita Galbiati, Maria Elena Cicardi, Marco Meroni, Veronica Ferrari, Barbara Tedesco, Margherita Piccolella, Elio Messi, Serena Carra, Angelo Poletti
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two neurodegenerative diseases in which similar pathogenic mechanisms are involved. Both diseases associate to the high propensity of specific misfolded proteins, like TDP-43 or FUS, to mislocalize and aggregate. This is partly due to their intrinsic biophysical properties and partly as a consequence of failure of the neuronal protein quality control (PQC) system. Several familial ALS/FTD cases are linked to an expansion of a repeated G4C2 hexanucleotide sequence present in the C9ORF72 gene...
June 12, 2017: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/28600885/immunolocalization-of-tar-dna-binding-protein-of-43%C3%A2-kda-tdp-43-in-mouse-seminiferous-epithelium
#9
Hari Prasad Osuru, Patcharin Pramoonjago, Mayuresh Abhyankar, Eric Swanson, LaToya Ann Roker, Helen Cathro, Prabhakara P Reddi
TDP-43 (TAR DNA-binding protein of 43 kDa) is an evolutionarily conserved, ubiquitously expressed, multi-functional DNA/RNA-binding protein with roles in gene transcription, mRNA splicing, stability, transport, micro RNA biogenesis, and suppression of transposons. Aberrant expression of TDP-43 in testis and sperm was recently shown to be associated with male infertility, which highlights the need to understand better the expression of TDP-43 in the testis. We previously cloned TDP-43 from a mouse testis cDNA library, and showed that it functions as a transcriptional repressor, and regulates the precise spatiotemporal expression of the Acrv1 gene, which encodes the acrosomal protein SP-10, during spermatogenesis...
June 10, 2017: Molecular Reproduction and Development
https://www.readbyqxmd.com/read/28599005/formation-and-spreading-of-tdp-43-aggregates-in-cultured-neuronal-and-glial-cells-demonstrated-by-time-lapse-imaging
#10
Tomohiro Ishii, Emiko Kawakami, Kentaro Endo, Hidemi Misawa, Kazuhiko Watabe
TAR DNA-binding protein 43 (TDP-43) is a main constituent of cytoplasmic aggregates in neuronal and glial cells in cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We have previously demonstrated that adenovirus-transduced artificial TDP-43 cytoplasmic aggregates formation is enhanced by proteasome inhibition in vitro and in vivo. However, the relationship between cytoplasmic aggregate formation and cell death remains unclear. In the present study, rat neural stem cell lines stably transfected with EGFP- or Sirius-expression vectors under the control of tubulin beta III, glial fibrillary acidic protein, or 2',3'-cyclic nucleotide 3'-phosphodiesterase promoter were differentiated into neurons, astrocytes, and oligodendrocytes, respectively, in the presence of retinoic acid...
2017: PloS One
https://www.readbyqxmd.com/read/28594853/the-unexpected-co-occurrence-of-grn-and-mapt-p-a152t-in-basque-families-clinical-and-pathological-characteristics
#11
Fermin Moreno, Begoña Indakoetxea, Myriam Barandiaran, María Cristina Caballero, Ana Gorostidi, Francesc Calafell, Alazne Gabilondo, Mikel Tainta, Miren Zulaica, José F Martí Massó, Adolfo López de Munain, Pascual Sánchez-Juan, Suzee E Lee
BACKGROUND: The co-occurrence of the c.709-1G>A GRN mutation and the p.A152T MAPT variant has been identified in 18 Basque families affected by frontotemporal dementia (FTD). We aimed to investigate the influence of the p.A152T MAPT variant on the clinical and neuropathological features of these Basque GRN families. METHODS AND FINDINGS: We compared clinical characteristics of 14 patients who carried the c.709-1G>A GRN mutation (GRN+/A152T-) with 21 patients who carried both the c...
2017: PloS One
https://www.readbyqxmd.com/read/28590932/tdp-43-hdac6-axis-promoted-tumor-progression-and-regulated-nutrient-deprivation-induced-autophagy-in-glioblastoma
#12
Tzu-Wei Lin, Ming-Teh Chen, Liang-Tin Lin, Pin-I Huang, Wen-Liang Lo, Yi-Ping Yang, Kai-Hsi Lu, Yi-Wei Chen, Shih-Hwa Chiou, Cheng-Wen Wu
Glioblastoma Multiforme (GBM) is a lethal primary brain tumor with poor survival lifespan and dismal outcome. Surgical resection of GBM is greatly limited due to the biological significance of brain, giving rise to tumor relapse in GBM patients. Transactive response DNA binding protein-43 (TDP-43) is a DNA/RNA-binding protein known for causing neurodegenerative diseases through post-translational modification; but little is known about its involvement in cancer development. In this study, we found that nutrient deprivation in GBM cell lines elevated TDP-43 expression by a mechanism of evasion from ubiquitin-dependent proteolytic pathway, and subsequently activated the autophagy process...
May 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28585542/loss-of-function-chchd10-mutations-in-cytoplasmic-tdp-43-accumulation-and-synaptic-integrity
#13
Jung-A A Woo, Tian Liu, Courtney Trotter, Cenxiao C Fang, Emillio De Narvaez, Patrick LePochat, Drew Maslar, Anusha Bukhari, Xingyu Zhao, Andrew Deonarine, Sandy D Westerheide, David E Kang
Although multiple CHCHD10 mutations are associated with the spectrum of familial and sporadic frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) diseases, neither the normal function of endogenous CHCHD10 nor its role in the pathological milieu (that is, TDP-43 pathology) of FTD/ALS have been investigated. In this study, we made a series of observations utilizing Caenorhabditis elegans models, mammalian cell lines, primary neurons and mouse brains, demonstrating that CHCHD10 normally exerts a protective role in mitochondrial and synaptic integrity as well as in the retention of nuclear TDP-43, whereas FTD/ALS-associated mutations (R15L and S59L) exhibit loss of function phenotypes in C...
June 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28575377/major-hnrnp-proteins-act-as-general-tdp-43-functional-modifiers-both-in-drosophila-and-human-neuronal-cells
#14
Chiara Appocher, Fatemeh Mohagheghi, Sara Cappelli, Cristiana Stuani, Maurizio Romano, Fabian Feiguin, Emanuele Buratti
Nuclear factor TDP-43 is known to play an important role in several neurodegenerative pathologies. In general, TDP-43 is an abundant protein within the eukaryotic nucleus that binds to many coding and non-coding RNAs and influence their processing. Using Drosophila, we have performed a functional screening to establish the ability of major hnRNP proteins to affect TDP-43 overexpression/depletion phenotypes. Interestingly, we observed that lowering hnRNP and TDP-43 expression has a generally harmful effect on flies locomotor abilities...
May 31, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28575052/myogenic-differentiation-of-vcp-disease-induced-pluripotent-stem-cells-a-novel-platform-for-drug-discovery
#15
Katrina J Llewellyn, Angèle Nalbandian, Lan N Weiss, Isabela Chang, Howard Yu, Bibo Khatib, Baichang Tan, Vanessa Scarfone, Virginia E Kimonis
Valosin Containing Protein (VCP) disease is an autosomal dominant multisystem proteinopathy caused by mutations in the VCP gene, and is primarily associated with progressive muscle weakness, including atrophy of the pelvic and shoulder girdle muscles. Currently, no treatments are available and cardiac and respiratory failures can lead to mortality at an early age. VCP is an AAA ATPase multifunction complex protein and mutations in the VCP gene resulting in disrupted autophagic clearance. Due to the rarity of the disease, the myopathic nature of the disorder, ethical and practical considerations, VCP disease muscle biopsies are difficult to obtain...
2017: PloS One
https://www.readbyqxmd.com/read/28566288/point-mutations-in-transactive-response-dna-binding-protein-43-tdp-43-s-n-terminal-domain-compromise-its-stability-dimerization-and-functions
#16
Miguel Mompeán, Valentina Romano, David Pantoja-Uceda, Cristiana Stuani, Francisco E Baralle, Emanuele Buratti, Douglas V Laurents
Transactive response DNA-binding protein 43 (TDP-43) performs multiple tasks in mRNA processing, transport and translational regulation, but it also forms aggregates implicated in amyotrophic lateral sclerosis (ALS). TDP-43's N-terminal domain (NTD) is important for these activities and dysfunctions; however, there is an open debate about whether or not it adopts a specifically folded, stable structure. Here, we studied NTD mutations designed to destabilize its structure utilizing NMR and fluorescence spectroscopies, analytical ultracentrifugation, splicing assays and in cell microscopy...
May 31, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28564594/progressive-motor-neuron-pathology-and-the-role-of-astrocytes-in-a-human-stem-cell-model-of-vcp-related-als
#17
Claire E Hall, Zhi Yao, Minee Choi, Giulia E Tyzack, Andrea Serio, Raphaelle Luisier, Jasmine Harley, Elisavet Preza, Charlie Arber, Sarah J Crisp, P Marc D Watson, Dimitri M Kullmann, Andrey Y Abramov, Selina Wray, Russell Burley, Samantha H Y Loh, L Miguel Martins, Molly M Stevens, Nicholas M Luscombe, Christopher R Sibley, Andras Lakatos, Jernej Ule, Sonia Gandhi, Rickie Patani
Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations of spinal cord MNs and ACs. We identify significantly increased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress...
May 30, 2017: Cell Reports
https://www.readbyqxmd.com/read/28560609/addition-of-exogenous-sod1-aggregates-causes-tdp-43-mislocalisation-and-aggregation
#18
Rafaa Zeineddine, Natalie E Farrawell, Isabella A Lambert-Smith, Justin J Yerbury
ALS is characterised by a focal onset of motor neuron loss, followed by contiguous outward spreading of pathology throughout the nervous system, resulting in paralysis and death generally within a few years after diagnosis. The aberrant release and uptake of toxic proteins including SOD1 and TDP-43 and their subsequent propagation, accumulation and deposition in motor neurons may explain such a pattern of pathology. Previous work has suggested that the internalization of aggregates triggers stress granule formation...
May 30, 2017: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/28550263/microglial-and-neuronal-tdp-43-pathology-in-anti-iglon5-related-tauopathy
#19
Annachiara Cagnin, Sara Mariotto, Michele Fiorini, Marina Gaule, Nicola Bonetto, Matteo Tagliapietra, Emanuele Buratti, Gianluigi Zanusso, Sergio Ferrari, Salvatore Monaco
A novel neuronal tauopathy, mainly confined to hypothalamus and brainstem tegmentum, has recently been reported in patients with autoantibodies to the neuronal cell-adhesion molecule IgLON5. We describe a patient with anti-IgLON5 syndrome, who presented with dysautonomia and sleep disorder, followed by subacute dementia. Postmortem brain examination disclosed neuronal tau pathology prevailing in the hippocampus, amygdala, and locus coeruleus, in addition to microglial/neuronal TDP-43 pathology, with overexpression of aberrantly phosphorylated forms and neurotoxic truncated fragments, in basal ganglia, nucleus basalis, thalamus, and midbrain...
May 26, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28550099/viral-delivery-of-c9orf72-hexanucleotide-repeat-expansions-in-mice-lead-to-repeat-length-dependent-neuropathology-and-behavioral-deficits
#20
Saul Herranz-Martin, Jayanth Chandran, Katherine Lewis, Padraig Mulcahy, Adrian Higginbottom, Callum Walker, Isabel Martinez-Pena Y Valenzuela, Ross A Jones, Ian Coldicott, Tommaso Iannitti, Mohammed Akaaboune, Sherif F El-Khamisy, Thomas H Gillingwater, Pamela J Shaw, Mimoun Azzouz
Intronic GGGGCC repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two major pathologies stemming from the hexanucleotide RNA expansions (HREs) have been identified in postmortem tissue: intracellular RNA foci and repeat-associated non-ATG dependent (RAN) dipeptides, though it is unclear how these and other hallmarks of disease contribute to the pathophysiology of neuronal injury. Here we generated two novel lines of mice that overexpress either 10 pure or 102 interrupted G4C2 repeats mediated by adeno-associated virus (AAV) and characterized relevant pathology and disease-related behavioral phenotypes...
May 26, 2017: Disease Models & Mechanisms
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