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Condition: ALS

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Total 36 results found since Jan 2013.

Identification of possible siRNA molecules for TDP43 mutants causing amyotrophic lateral sclerosis: In silico design and molecular dynamics study.
Abstract The DNA binding protein, TDP43 is a major protein involved in amyotrophic lateral sclerosis and other neurological disorders such as frontotemporal dementia, Alzheimer disease, etc. In the present study, we have designed possible siRNAs for the glycine rich region of tardbp mutants causing ALS disorder based on a systematic theoretical approach including (i) identification of respective codons for all mutants (reported at the protein level) based on both minimum free energy and probabilistic approaches, (ii) rational design of siRNA, (iii) secondary structure analysis for the target accessibility of siRNA...
Source: Computational Biology and Chemistry - January 23, 2016 Category: Bioinformatics Authors: Bhandare VV, Ramaswamy A Tags: Comput Biol Chem Source Type: research

Genome-wide siRNA screening reveals that DCAF4-mediated ubiquitination of optineurin stimulates autophagic degradation of Cu,Zn-superoxide dismutase Cell Biology
Cu, Zn superoxide dismutase (SOD1) is one of the genes implicated in the devastating neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Although the precise mechanisms of SOD1 mutant (SOD1mut)-induced motoneuron toxicity are still unclear, defects in SOD1 proteostasis are known to have a critical role in ALS pathogenesis. We previously reported that the SOD1mut adopts a conformation that exposes a Derlin-1–binding region (DBR) and that DBR-exposed SOD1 interacts with Derlin-1, leading to motoneuron death. We also found that an environmental change, i.e. zinc depletion, induces a conformational change in WT S...
Source: Journal of Biological Chemistry - March 5, 2020 Category: Chemistry Authors: Kengo Homma, Hiromitsu Takahashi, Naomi Tsuburaya, Isao Naguro, Takao Fujisawa, Hidenori Ichijo Tags: Molecular Bases of Disease Source Type: research

Naringenin Produces Neuroprotection Against LPS-Induced Dopamine Neurotoxicity via the Inhibition of Microglial NLRP3 Inflammasome Activation
Conclusions: This study demonstrated that NAR targeted microglial NLRP3 inflammasome to protect DA neurons against LPS-induced neurotoxicity. These findings suggest NAR might hold a promising therapeutic potential for PD. Background Parkinson's disease (PD) is the second most prevalent central nervous system (CNS) degenerative disease. It is characterized by slow and progressive loss of dopamine (DA) neurons in the midbrain substantia nigra (SN) with the accumulation of α-synuclein in Lewy bodies and neuritis (1). Although the etiology of PD remains unclear, amounts of studies have suggested that ne...
Source: Frontiers in Immunology - April 30, 2019 Category: Allergy & Immunology Source Type: research

Structural Dynamics of Human Argonaute2 and Its Interaction with siRNAs Designed to Target Mutant tdp43.
Authors: Bhandare V, Ramaswamy A Abstract The human Argonaute2 protein (Ago2) is a key player in RNA interference pathway and small RNA recognition by Ago2 is the crucial step in siRNA mediated gene silencing mechanism. The present study highlights the structural and functional dynamics of human Ago2 and the interaction mechanism of Ago2 with a set of seven siRNAs for the first time. The human Ago2 protein adopts two conformations such as "open" and "close" during the simulation of 25 ns. One of the domains named as PAZ, which is responsible for anchoring the 3'-end of siRNA guide strand, is observed as a highly fl...
Source: Advances in Bioinformatics - April 26, 2016 Category: Bioinformatics Tags: Adv Bioinformatics Source Type: research

δ‐Opioid Receptors Up‐regulate Excitatory Amino Acid Transporters in Mouse Astrocytes
Conclusions and ImplicationsDOR activation upregulates astrocytic EAATs via MEK‐ERK‐p38 signaling, suggesting a critical role of DOR in the regulation of astrocytic EAATs and neuroprotection against excitotoxic injury. Since decreased EAAT expression contributes to pathophysiology in many neurological diseases such as amyotrophic lateral sclerosis, our findings present a new platform for potential treatments of these diseases.
Source: British Journal of Pharmacology - July 23, 2014 Category: Drugs & Pharmacology Authors: Jianfeng Liang, Dongman Chao, Harleen K Sandhu, Yanbing Yu, Li Zhang, Gianfranco Balboni, Dong H Kim, Ying Xia Tags: Research Paper Source Type: research

The JAK/STAT Pathway in Skeletal Muscle Pathophysiology
Conclusion and Perspectives The IL-6/JAK/STAT signaling cascade plays a dominant role in skeletal muscle pathophysiology. IL-6 autocrine, paracrine, and endocrine functions assign to its downstream effectors pivotal importance in skeletal muscle-wasting-associated diseases and other multiple system diseases where muscle acts in communication with other organs. Targeting the components of the JAK/STAT pathway recently emerged as a strategic approach for the treatment of inflammatory diseases and human cancer. This review highlights the opposite outcomes on muscle biology caused by the amount of local and systemic release ...
Source: Frontiers in Physiology - April 29, 2019 Category: Physiology Source Type: research

TDP-43 knockdown causes innate immune activation via protein kinase R in astrocytes.
Abstract TAR-DNA binding protein 43 (TDP-43) is a multifunctional RNA binding protein directly implicated in the etiology of amyotrophic lateral sclerosis (ALS). Previous studies have demonstrated that loss of TDP-43 function leads to intracellular accumulation of non-coding repetitive element transcripts and double-stranded RNA (dsRNA). These events could cause immune activation and contribute to the neuroinflammation observed in ALS, but this possibility has not been investigated. Here, we knock down TDP-43 in primary rat astrocytes via siRNA, and we use RNA-seq, immunofluorescence, and immunoblotting to show th...
Source: Neurobiology of Disease - June 19, 2019 Category: Neurology Authors: LaRocca TJ, Mariani A, Watkins LR, Link CD Tags: Neurobiol Dis Source Type: research

Optineurin suppression causes neuronal cell death via NF‐κB pathway
This article is protected by copyright. All rights reserved.
Source: Journal of Neurochemistry - June 1, 2013 Category: Neurology Authors: Mayumi Akizuki, Hirofumi Yamashita, Kengo Uemura, Hirofumi Maruyama, Hideshi Kawakami, Hidefumi Ito, Ryosuke Takahashi Tags: Short Communication Source Type: research

Functional Interaction between Amyloid-β Precursor Protein and Peripherin Neurofilaments: A Shared Pathway Leading to Alzheimer's Disease and Amyotrophic Lateral Sclerosis?
Conclusion: Our results indicate that a fraction of APP is cleaved by β-secretase in the soma and that the generated sAPP becomes associated with perinuclear peripherin neurofilaments. These findings link the metabolism of APP - which is dysregulated in AD - to the organization of neurofilaments - which is abnormal in ALS - and suggest a possible crosstalk/overlap between the molecular mechanisms of these diseases. PMID: 24009040 [PubMed - as supplied by publisher]
Source: Neuro-Degenerative Diseases - September 4, 2013 Category: Neurology Authors: Muresan V, Villegas C, Ladescu Muresan Z Tags: Neurodegener Dis Source Type: research

VAPB/ALS8 interacts with FFAT-like proteins including the p97 cofactor FAF1 and the ASNA1 ATPase
Conclusions: The FFAT-like motifs we identified in FAF1 and ASNA1 demonstrate that sequences containing a single phenylalanine residue with the consensus (D/E)(D/E)FEDAx(D/E) are also proficient to mediate interaction with VAPB.Our findings indicate that the repertoire of VAPB interactors is more diverse than previously anticipated and link VAPB to the function of ATPase complexes such as p97/FAF1 and ASNA1/TRC.
Source: BMC Biology - Latest articles - May 29, 2014 Category: Biology Authors: Yorann BaronPatrick PedrioliKshitiz TyagiClare JohnsonNicola WoodDaniel FountaineMelanie WightmanGabriela Alexandru Source Type: research

TARDBP pathogenic mutations increase cytoplasmic translocation of TDP-43 and cause reduction of endoplasmic reticulum Ca(2+) signaling in motor neurons.
Abstract The transactive response DNA binding protein (TDP-43) is a major component of the characteristic neuronal cytoplasmic inclusions seen in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Furthermore, pathogenic mutations in the gene encoding TDP-43, TARDBP, are found in sporadic and familial ALS cases. To study the molecular mechanisms of cellular toxicity due to TDP-43 mutations we generated a novel in vitro cellular model using a fluorescently tagged human genomic TARDBP locus carrying one of two ALS-associated mutations, A382T or M337V, which were used to generate site-specific bac...
Source: Neurobiology of Disease - December 17, 2014 Category: Neurology Authors: Mutihac R, Alegre-Abarrategui J, Gordon D, Farrimond L, Yamasaki-Mann M, Talbot K, Wade-Martins R Tags: Neurobiol Dis Source Type: research

Phosphorylation of hnRNP K by cyclin-dependent kinase 2 controls cytosolic accumulation of TDP-43
Cytosolic accumulation of TAR DNA binding protein 43 (TDP-43) is a major neuropathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the mechanisms involved in TDP-43 accumulation remain largely unknown. Previously, we reported that inhibitors of cyclin-dependent kinases (CDKs) prevented cytosolic stress granule accumulation of TDP-43, correlating with depletion of heterogeneous ribonucleoprotein (hnRNP) K from stress granules. In the present study, we further investigated the relationship between TDP-43 and hnRNP K and their control by CDKs. Inhibition of CDK2 ab...
Source: Human Molecular Genetics - February 19, 2015 Category: Genetics & Stem Cells Authors: Moujalled, D., James, J. L., Yang, S., Zhang, K., Duncan, C., Moujalled, D. M., Parker, S. J., Caragounis, A., Lidgerwood, G., Turner, B. J., Atkin, J. D., Grubman, A., Liddell, J. R., Proepper, C., Boeckers, T. M., Kanninen, K. M., Blair, I., Crouch, P. Tags: ARTICLES Source Type: research

Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate
Publication date: 20 August 2015 Source:Neuroscience, Volume 301 Author(s): S.-Y. Wang , M. Ren , H.-Z. Jiang , J. Wang , H.-Q. Jiang , X. Yin , Y. Qi , X.-D. Wang , G.-T. Dong , T.-H. Wang , Y.-Q. Yang , H.-L. Feng Amyotrophic lateral sclerosis (ALS) is an idiopathic and lethal neurodegenerative disease that currently has no effective treatment. A recent study found that the Notch signaling pathway was up-regulated in a TAR DNA-binding protein-43 (TDP-43) Drosophila model of ALS. Notch signaling acts as a master regulator in the central nervous system. However, the mechanisms by which Notch participates in the pathogene...
Source: Neuroscience - June 26, 2015 Category: Neuroscience Source Type: research

An amyotrophic lateral sclerosis-linked mutation in GLE1 alters the cellular pool of human Gle1 functional isoforms
Publication date: Available online 11 November 2015 Source:Advances in Biological Regulation Author(s): Aditi, Laura Glass, T. Renee Dawson, Susan R. Wente Amyotrophic lateral sclerosis (ALS) is a lethal late onset motor neuron disease with underlying cellular defects in RNA metabolism. In prior studies, two deleterious heterozygous mutations in the gene encoding human (h)Gle1 were identified in ALS patients. hGle1 is an mRNA processing modulator that requires inositol hexakisphosphate (IP6) binding for function. Interestingly, one hGLE1 mutation (c.1965-2A>C) results in a novel 88 amino acid C-terminal insert...
Source: Advances in Biological Regulation - November 13, 2015 Category: Biology Source Type: research

Electrophilic nitro-fatty acids prevent astrocyte-mediated toxicity to motor neurons in a cell model of familial amyotrophic lateral sclerosis via nuclear factor erythroid 2-related factor activation.
Abstract Nitro-fatty acids (NO2-FA) are electrophilic signaling mediators formed in tissues during inflammation, which are able to induce pleiotropic cytoprotective and antioxidant pathways including up regulation of Nuclear factor erythroid 2-related factor 2 (Nrf2) responsive genes. Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons associated to an inflammatory process that usually aggravates the disease progression. In ALS animal models, the activation of the transcription factor Nrf2 in astrocytes confers protection to neighboring neurons. It is...
Source: Free Radical Biology and Medicine - March 20, 2016 Category: Biology Authors: Diaz-Amarilla P, Miquel E, Trostchansky A, Trias E, Ferreira AM, Freeman BA, Cassina P, Barbeito L, Vargas MR, Rubbo H Tags: Free Radic Biol Med Source Type: research