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https://www.readbyqxmd.com/read/28539470/the-src-c-abl-pathway-is-a-potential-therapeutic-target-in-amyotrophic-lateral-sclerosis
#1
Keiko Imamura, Yuishin Izumi, Akira Watanabe, Kayoko Tsukita, Knut Woltjen, Takuya Yamamoto, Akitsu Hotta, Takayuki Kondo, Shiho Kitaoka, Akira Ohta, Akito Tanaka, Dai Watanabe, Mitsuya Morita, Hiroshi Takuma, Akira Tamaoka, Tilo Kunath, Selina Wray, Hirokazu Furuya, Takumi Era, Kouki Makioka, Koichi Okamoto, Takao Fujisawa, Hideki Nishitoh, Kengo Homma, Hidenori Ichijo, Jean-Pierre Julien, Nanako Obata, Masato Hosokawa, Haruhiko Akiyama, Satoshi Kaneko, Takashi Ayaki, Hidefumi Ito, Ryuji Kaji, Ryosuke Takahashi, Shinya Yamanaka, Haruhisa Inoue
Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro...
May 24, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28537433/aspirin-mediated-acetylation-protects-against-multiple-neurodegenerative-pathologies-by-impeding-protein-aggregation
#2
Srinivas Ayyadevara, Meenakshisundaram Balasubramaniam, Ramani Alla, J L Mehta, Robert J Shmookler Reis
AIMS: Many progressive neurological disorders, including Alzheimer's, Huntington's, and Parkinson's diseases, are characterized by accumulation of insoluble protein aggregates. In prospective trials, the cyclooxygenase inhibitor aspirin (acetylsalicylic acid) reduced the risk of Alzheimer's and Parkinson's diseases, as well as cardiovascular events and many late-onset cancers. In view of previous evidence that inflammation promotes protein hyperphosphorylation and aggregation in neurodegenerative diseases, we asked whether aspirin's known ability to block phosphorylation may be secondary to its acetylation of protein targets...
May 24, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28532818/tdp-43-upregulation-mediated-by-the-nlrp3-inflammasome-induces-cognitive-impairment-in-2-2-4-4-tetrabromodiphenyl-ether-bde-47-treated-mice
#3
Juan Zhuang, Xin Wen, Yan-Qiu Zhang, Qun Shan, Zi-Feng Zhang, Gui-Hong Zheng, Shao-Hua Fan, Meng-Qiu Li, Dong-Mei Wu, Bin Hu, Jun Lu, Yuan-Lin Zheng
It is now commonly known that exposure to polybrominated diphenyl ethers (PBDEs) may cause neurotoxicity and cognitive deficits in children as well as adults, but the underlying mechanisms are still not clear. In the present study, we aimed to elucidate the potential underlying mechanism of 2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47)-induced neurotoxicity and cognitive impairment. Our results showed that BDE-47-treated mice exhibited impaired cognition and robust upregulation of nuclear TDP-43 in the hippocampus...
May 19, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28531192/overexpression-of-the-essential-sis1-chaperone-reduces-tdp-43-effects-on-toxicity-and-proteolysis
#4
Sei-Kyoung Park, Joo Y Hong, Fatih Arslan, Vydehi Kanneganti, Basant Patel, Alex Tietsort, Elizabeth M H Tank, Xingli Li, Sami J Barmada, Susan W Liebman
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by selective loss of motor neurons with inclusions frequently containing the RNA/DNA binding protein TDP-43. Using a yeast model of ALS exhibiting TDP-43 dependent toxicity, we now show that TDP-43 overexpression dramatically alters cell shape and reduces ubiquitin dependent proteolysis of a reporter construct. Furthermore, we show that an excess of the Hsp40 chaperone, Sis1, reduced TDP-43's effect on toxicity, cell shape and proteolysis...
May 22, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28521037/clinical-significance-of-tdp-43-neuropathology-in-amyotrophic-lateral-sclerosis
#5
Matthew D Cykowski, Suzanne Z Powell, Leif E Peterson, Joan W Appel, Andreana L Rivera, Hidehiro Takei, Ellen Chang, Stanley H Appel
To determine the significance of TAR DNA binding protein 43 kDa (TDP-43) pathology in amyotrophic lateral sclerosis (ALS), we examined the whole brains and spinal cords of 57 patients (35 men; 22 women; mean age 63.3 years; 15 patients with c9orf72-associated ALS [c9ALS]). TDP-43 pathologic burden was determined relative to symptom onset site, disease duration, progression rate, cognitive status, and c9ALS status. There was a trend for greater TDP-43 pathologic burden in cognitively impaired patients (p = 0...
May 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28510586/truncation-of-the-tar-dna-binding-protein-43-is-not-a-prerequisite-for-cytoplasmic-relocalization-and-is-suppressed-by-caspase-inhibition-and-by-introduction-of-the-a90v-sequence-variant
#6
Heike J Wobst, Louise Delsing, Nicholas J Brandon, Stephen J Moss
The RNA-binding and -processing protein TAR DNA-binding protein 43 (TDP-43) is heavily linked to the underlying causes and pathology of neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In these diseases, TDP-43 is mislocalized, hyperphosphorylated, ubiquitinated, aggregated and cleaved. The importance of TDP-43 cleavage in the disease pathogenesis is still poorly understood. Here we detail the use of D-sorbitol as an exogenous stressor that causes TDP-43 cleavage in HeLa cells, resulting in a 35 kDa truncated product that accumulates in the cytoplasm within one hour of treatment...
2017: PloS One
https://www.readbyqxmd.com/read/28510254/effects-of-mutant-tdp-43-on-the-nrf2-are-pathway-and-protein-expression-of-mafk-and-jdp2-in-nsc-34-cells
#7
Y P Tian, F Y Che, Q P Su, Y C Lu, C P You, L M Huang, S G Wang, L Wang, J X Yu
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons and lacks an effective treatment. The disease pathogenesis has not been clarified at present. Pathological transactive response DNA-binding protein 43 (TDP-43) plays an important role in the pathogenesis of ALS. Nuclear translocation of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is found in a mutant TDP-43 transgenic cell model, but its downstream antioxidant enzyme expression is decreased. To elucidate the specific mechanism of Nrf2/ARE (antioxidant responsive element) signaling dysfunction, we constructed an ALS cell model with human mutant TDP-43 using the NSC-34 cell line to evaluate the impact of the TDP-43 mutation on the Nrf2/ARE pathway...
May 10, 2017: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/28497562/different-aggregation-states-of-a-nuclear-localization-signal-tagged-25-kda-c-terminal-fragment-of-tar-rna-dna-binding-protein-43%C3%A2-kda
#8
Akira Kitamura, Sachiko Yuno, Hideki Muto, Masataka Kinjo
The mechanism and cause of motor neuronal cell death in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder, are unknown; gain of function of oligomers and aggregation of misfolded proteins, including carboxyl-terminal fragments (CTFs) of TAR RNA/DNA-binding protein 43 kDa (TDP-43), have been proposed as important causative factors in the onset of ALS. We recently reported that a nuclear localization signal (NLS)-tagged 25-kDa CTF of TDP-43 (TDP25) could decrease the cell-death proportion compared with that promoted by TDP25...
May 12, 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/28488154/impact-of-multiple-pathologies-on-the-threshold-for-clinically-overt-dementia
#9
REVIEW
Alifiya Kapasi, Charles DeCarli, Julie A Schneider
Longitudinal clinical-pathological studies have increasingly recognized the importance of mixed pathologies (the coexistence of one or more neurodegenerative and cerebrovascular disease pathologies) as important factors in the development of Alzheimer's disease (AD) and other forms of dementia. Older persons with AD pathology, often have concomitant cerebrovascular disease pathologies (macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy) as well as other concomitant neurodegenerative disease pathologies (Lewy bodies, TDP-43, hippocampal sclerosis)...
May 9, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28487370/transactive-response-dna-binding-protein-43-tdp-43-regulates-alternative-splicing-of-tau-exon-10-implications-for-the-pathogenesis-of-tauopathies
#10
Jianlan Gu, Feng Chen, Khalid Iqbal, Cheng-Xin Gong, Xinglong Wang, Fei Liu
Hyperphosphorylation and aggregation of the neuronal protein tau is responsible for neurodegenerative diseases called tauopathies. Dysregulation of the alternative splicing of the exon 10 results in alterations of the ratio of two tau isoforms, 3R-tau and 4R-tau, which have been seen in several tauopathies. Transactive response DNA-binding protein 43 kDa (TDP-43) is involved in the regulation of RNA processing, including splicing. Cytoplasmic aggregation of TDP-43 has been observed in the brains of individuals with chronic traumatic encephalopathy or Alzheimer's disease, diseases in which neurofibrillary tangles of hyperphosphorylated tau are hallmarks...
May 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28486039/flow-cytometric-measurement-of-the-cellular-propagation-of-tdp-43-aggregation
#11
Rafaa Zeineddine, Daniel R Whiten, Natalie E Farrawell, Luke McAlary, Maya A Hanspal, Janet R Kumita, Mark R Wilson, Justin J Yerbury
Amyotrophic lateral sclerosis is a devastating neuromuscular degenerative disease characterized by a focal onset of motor neuron loss, followed by contiguous outward spreading of pathology including TAR DNA-binding protein of 43 kDa (TDP-43) aggregates. Previous work suggests that TDP-43 can move between cells. Here we used a novel flow cytometry technique (FloIT) to analyze TDP-43 inclusions and propagation. When cells were transfected to express either mutant G294A TDP-43 fused to GFP or wild type TDP-43fused to tomato red and then co-cultured, flow cytometry detected intact cells containing both fusion proteins and using FloIT detected an increase in the numbers of inclusions in lysates from cells expressing wild type TDP-43-tomato...
May 9, 2017: Prion
https://www.readbyqxmd.com/read/28482850/mutant-tdp-43-does-not-impair-mitochondrial-bioenergetics-in-vitro-and-in-vivo
#12
Hibiki Kawamata, Pablo Peixoto, Csaba Konrad, Gloria Palomo, Kirsten Bredvik, Meri Gerges, Federica Valsecchi, Leonard Petrucelli, John M Ravits, Anatoly Starkov, Giovanni Manfredi
BACKGROUND: Mitochondrial dysfunction has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Functional studies of mitochondrial bioenergetics have focused mostly on superoxide dismutase 1 (SOD1) mutants, and showed that mutant human SOD1 impairs mitochondrial oxidative phosphorylation, calcium homeostasis, and dynamics. However, recent reports have indicated that alterations in transactivation response element DNA-binding protein 43 (TDP-43) can also lead to defects of mitochondrial morphology and dynamics...
May 8, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28476168/dioxins-and-related-environmental-contaminants-increase-tdp-43-levels
#13
Peter E A Ash, Elizabeth A Stanford, Ali Al Abdulatif, Alejandra Ramirez-Cardenas, Heather I Ballance, Samantha Boudeau, Amanda Jeh, James M Murithi, Yorghos Tripodis, George J Murphy, David H Sherr, Benjamin Wolozin
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative condition that is characterized by progressive loss of motor neurons and the accumulation of aggregated TAR DNA Binding Protein-43 (TDP-43, gene: TARDBP). Increasing evidence indicates that environmental factors contribute to the risk of ALS. Dioxins, related planar polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) are environmental contaminants that activate the aryl hydrocarbon receptor (AHR), a ligand-activated, PAS family transcription factor...
May 5, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28473694/accumulation-of-multiple-neurodegenerative-disease-related-proteins-in-familial-frontotemporal-lobar-degeneration-associated-with-granulin-mutation
#14
Masato Hosokawa, Hiromi Kondo, Geidy E Serrano, Thomas G Beach, Andrew C Robinson, David M Mann, Haruhiko Akiyama, Masato Hasegawa, Tetsuaki Arai
In 2006, mutations in the granulin gene were identified in patients with familial Frontotemporal Lobar Degeneration. Granulin transcript haploinsufficiency has been proposed as a disease mechanism that leads to the loss of functional progranulin protein. Granulin mutations were initially found in tau-negative patients, though recent findings indicate that these mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer's disease and corticobasal degeneration. Moreover, a reduction in progranulin in tau transgenic mice is associated with increasing tau accumulation...
May 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28472174/augmented-quantal-release-of-acetylcholine-at-the-vertebrate-neuromuscular-junction-following-tdp-43-depletion
#15
Stefania Dzieciolowska, Pierre Drapeau, Gary Alan Barclay Armstrong
TAR DNA binding protein (TDP-43) is a 43 kD, predominately nuclear, protein involved in RNA metabolism. Of clinical significance is that the majority of amyotrophic lateral sclerosis (ALS) patients display abnormal accumulation of misfolded TDP-43 in the cytoplasm, which is coincident with a loss of nuclear localization in the afflicted regions of the central nervous system. Little is known about defects that arise in loss-of-function models, in particular synaptic defects that arise at the neuromuscular junction (NMJ)...
2017: PloS One
https://www.readbyqxmd.com/read/28467899/high-resolution-rna-maps-suggest-common-principles-of-splicing-and-polyadenylation-regulation-by-tdp-43
#16
Gregor Rot, Zhen Wang, Ina Huppertz, Miha Modic, Tina Lenče, Martina Hallegger, Nejc Haberman, Tomaž Curk, Christian von Mering, Jernej Ule
Many RNA-binding proteins (RBPs) regulate both alternative exons and poly(A) site selection. To understand their regulatory principles, we developed expressRNA, a web platform encompassing computational tools for integration of iCLIP and RNA motif analyses with RNA-seq and 3' mRNA sequencing. This reveals at nucleotide resolution the "RNA maps" describing how the RNA binding positions of RBPs relate to their regulatory functions. We use this approach to examine how TDP-43, an RBP involved in several neurodegenerative diseases, binds around its regulated poly(A) sites...
May 2, 2017: Cell Reports
https://www.readbyqxmd.com/read/28467211/hippocampal-sclerosis-in-older-patients-practical-examples-and-guidance-with-a-focus-on-cerebral-age-related-tdp-43-with-sclerosis
#17
Matthew D Cykowski, Suzanne Z Powell, Paul E Schulz, Hidehiro Takei, Andreana L Rivera, Robert E Jackson, Gustavo Roman, Gregory A Jicha, Peter T Nelson
CONTEXT: - Autopsy studies of the older population (≥65 years of age), and particularly of the "oldest-old" (≥85 years of age), have identified a significant proportion (∼20%) of cognitively impaired patients in which hippocampal sclerosis is the major substrate of an amnestic syndrome. Hippocampal sclerosis may also be comorbid with frontotemporal lobar degeneration, Alzheimer disease, and Lewy body disease. Until recently, the terms hippocampal sclerosis of aging or hippocampal sclerosis dementia were applied in this context...
May 3, 2017: Archives of Pathology & Laboratory Medicine
https://www.readbyqxmd.com/read/28466273/tdp-43-and-cytoskeletal-proteins-in-als
#18
REVIEW
Moritz Oberstadt, Joseph Claßen, Thomas Arendt, Max Holzer
Amyotrophic lateral sclerosis (ALS) represents a rapidly progressing neurodegenerative disease and is characterized by a degeneration of motor neurons. Motor neurons are particularly susceptible to selective and early degeneration because of their extended axon length and their dependency on the cytoskeleton for its stability, signaling, and axonal transport. The motor neuron cytoskeleton comprises actin filaments, neurofilaments like peripherin, and microtubules. The Transactivating Response Region (TAR) DNA Binding Protein (TDP-43) forms characteristic cytoplasmic aggregates in motor neurons of ALS patients, and at least in part, the pathogenesis of ALS seems to be driven by toxic pTDP-43 aggregates in cytoplasm, which lead to a diminished axon formation and reduced axon length...
May 2, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28466142/reappraisal-of-tdp-43-pathology-in-ftld-u-subtypes
#19
Ian R Mackenzie, Manuela Neumann
Frontotemporal lobar degeneration with tau-negative, ubiquitin-immunoreactive (-ir) pathology (FTLD-U) is subclassified based on the type and cortical laminar distribution of neuronal inclusions. Following the discovery of the transactive response DNA-binding protein Mr 43 kD (TDP-43) as the ubiquitinated protein in most FTLD-U, the same pathological criteria have been used to classify FTLD cases based on TDP-43-ir changes. However, the fact that immunohistochemistry (IHC) for ubiquitin and TDP-43 each recognizes slightly different pathological changes in these cases means that the original FTLD-U subtype criteria may not be directly applicable for use with TDP-43 IHC...
May 2, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28460069/cognitive-reserve-and-tmem106b-genotype-modulate-brain-damage-in-presymptomatic-frontotemporal-dementia-a-genfi-study
#20
Enrico Premi, Mario Grassi, John van Swieten, Daniela Galimberti, Caroline Graff, Mario Masellis, Carmela Tartaglia, Fabrizio Tagliavini, James B Rowe, Robert Laforce, Elizabeth Finger, Giovanni B Frisoni, Alexandre de Mendonça, Sandro Sorbi, Stefano Gazzina, Maura Cosseddu, Silvana Archetti, Roberto Gasparotti, Marta Manes, Antonella Alberici, Manuel J Cardoso, Martina Bocchetta, David M Cash, Sebastian Ourselin, Alessandro Padovani, Jonathan D Rohrer, Barbara Borroni
Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology...
April 27, 2017: Brain: a Journal of Neurology
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