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https://www.readbyqxmd.com/read/28197542/the-proline-arginine-dipeptide-from-hexanucleotide-repeat-expanded-c9orf72-inhibits-the-proteasome
#1
Rahul Gupta, Matthews Lan, Jelena Mojsilovic-Petrovic, Won Hoon Choi, Nathaniel Safren, Sami Barmada, Min Jae Lee, Robert Kalb
An intronic hexanucleotide repeat expansion (HRE) mutation in the C9ORF72 gene is the most common cause of familial ALS and frontotemporal dementia (FTD) and is found in ∼7% of individuals with apparently sporadic disease. Several different diamino acid peptides can be generated from the HRE by noncanonical translation (repeat-associated non-ATG translation, or RAN translation), and some of these peptides can be toxic. Here, we studied the effects of two arginine containing RAN translation products [proline/arginine repeated 20 times (PR20) and glycine/arginine repeated 20 times (GR20)] in primary rat spinal cord neuron cultures grown on an astrocyte feeder layer...
January 2017: ENeuro
https://www.readbyqxmd.com/read/28167899/cysteine-modifications-in-the-pathogenesis-of-als
#2
REVIEW
Cristiana Valle, Maria Teresa Carrì
Several proteins are found misfolded and aggregated in sporadic and genetic forms of amyotrophic lateral sclerosis (ALS). These include superoxide dismutase (SOD1), transactive response DNA-binding protein (TDP-43), fused in sarcoma/translocated in liposarcoma protein (FUS/TLS), p62, vasolin-containing protein (VCP), Ubiquilin-2 and dipeptide repeats produced by unconventional RAN-translation of the GGGGCC expansion in C9ORF72. Up to date, functional studies have not yet revealed a common mechanism for the formation of such diverse protein inclusions...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28163215/vegf-alleviates-als-csf-induced-cytoplasmic-accumulations-of-tdp-43-and-fus-tls-in-nsc-34-cells
#3
Shubham Shantanu, K Vijayalakshmi, S Shruthi, B K Chandrasekhar Sagar, T N Sathyaprabha, A Nalini, Trichur R Raju, Phalguni Anand Alladi
Cytoplasmic mislocalisation and aggregation of TDP-43 and FUS/TLS proteins in spinal motor neurons contribute to the pathogenesis of the highly fatal disorder amyotrophic lateral sclerosis (ALS). We investigated the neuroprotective effect of VEGF on expression of these proteins in the motor neuronal cell line NSC-34 modelled to reminisce sporadic form of ALS. We studied the expression of TDP-43 and FUS/TLS proteins after exposure to ALS-CSF and following VEGF supplementation by quantitative confocal microscopy and electron microscopy...
February 2, 2017: Journal of Chemical Neuroanatomy
https://www.readbyqxmd.com/read/28163193/the-neuropathological-signature-of-bulbar-onset-als-a-systematic-review
#4
REVIEW
S Shellikeri, V Karthikeyan, R Martino, S E Black, L Zinman, J Keith, Y Yunusova
ALS is a multisystem disorder affecting cognitive and motor functions. Bulbar-onset ALS (bALS) may be preferentially associated with language/cognitive impairments, compared with spinal-onset ALS (sALS), stemming from a potentially unique neuropathology. The objective of this systematic review was to compare neuropathology reported for bALS and sALS subtypes in studies of cadaveric brains. Using Cochrane guidelines, we reviewed articles in MEDLINE, Embase, and PsycINFO databases using standardized search terms for ALS and neuropathology, from inception until July 16th 2016...
February 2, 2017: Neuroscience and Biobehavioral Reviews
https://www.readbyqxmd.com/read/28007900/extensive-cryptic-splicing-upon-loss-of-rbm17-and-tdp43-in-neurodegeneration-models
#5
Qiumin Tan, Hari Krishna Yalamanchili, Jeehye Park, Antonia De Maio, Hsiang-Chih Lu, Ying-Wooi Wan, Joshua J White, Vitaliy V Bondar, Layal S Sayegh, Xiuyun Liu, Yan Gao, Roy V Sillitoe, Harry T Orr, Zhandong Liu, Huda Y Zoghbi
Splicing regulation is an important step of post-transcriptional gene regulation. It is a highly dynamic process orchestrated by RNA-binding proteins (RBPs). RBP dysfunction and global splicing dysregulation have been implicated in many human diseases, but the in vivo functions of most RBPs and the splicing outcome upon their loss remain largely unexplored. Here we report that constitutive deletion of Rbm17, which encodes an RBP with a putative role in splicing, causes early embryonic lethality in mice and that its loss in Purkinje neurons leads to rapid degeneration...
October 7, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27915998/an-update-on-semantic-dementia-genetics-imaging-and-pathology
#6
REVIEW
Ramon Landin-Romero, Rachel Tan, John R Hodges, Fiona Kumfor
Progressive and relatively circumscribed loss of semantic knowledge, referred to as semantic dementia (SD) which falls under the broader umbrella of frontotemporal dementia, was officially identified as a clinical syndrome less than 50 years ago. Here, we review recent neuroimaging, pathological, and genetic research in SD. From a neuroimaging perspective, SD is characterised by hallmark asymmetrical atrophy of the anterior temporal pole and anterior fusiform gyrus, which is usually left lateralised. Functional magnetic resonance imaging (fMRI) studies have revealed widespread changes in connectivity, implicating the anterior temporal regions in semantic deficits in SD...
December 5, 2016: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/27871485/unusual-processing-generates-spa-lncrnas-that-sequester-multiple-rna-binding-proteins
#7
Huang Wu, Qing-Fei Yin, Zheng Luo, Run-Wen Yao, Chuan-Chuan Zheng, Jun Zhang, Jian-Feng Xiang, Li Yang, Ling-Ling Chen
We identify a type of polycistronic transcript-derived long noncoding RNAs (lncRNAs) that are 5' small nucleolar RNA (snoRNA) capped and 3' polyadenylated (SPAs). SPA processing is associated with nascent mRNA 3' processing and kinetic competition between XRN2 trimming and Pol II elongation. Following cleavage/polyadenylation of its upstream gene, the downstream uncapped pre-SPA is trimmed by XRN2 until this exonuclease reaches the co-transcriptionally assembled snoRNP. This snoRNP complex prevents further degradation, generates a snoRNA 5' end, and allows continuous Pol II elongation...
November 3, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27849576/two-familial-als-proteins-function-in-prevention-repair-of-transcription-associated-dna-damage
#8
Sarah J Hill, Daniel A Mordes, Lisa A Cameron, Donna S Neuberg, Serena Landini, Kevin Eggan, David M Livingston
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27767988/a-novel-loss-of-function-grn-mutation-p-tyr229-%C3%A2-clinical-and-neuropathological-features
#9
Liina Kuuluvainen, Minna Pöyhönen, Petra Pasanen, Maija Siitonen, Jaana Rummukainen, Pentti J Tienari, Anders Paetau, Liisa Myllykangas
Mutations in the progranulin (GRN) gene represent about 5-10% of frontotemporal lobar degeneration (FTLD). We describe a proband with a novel GRN mutation c.687T>A, p.(Tyr229*), presenting with dyspraxia, dysgraphia, and dysphasia at the age of 60 and a very severe FTLD neuropathological phenotype with TDP43 inclusions. The nephew of the proband had signs of dementia and personality changes at the age of 60 and showed similar but milder FTLD pathology. Three other family members had had early-onset dementia...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27687581/sod1-dimerization-monitoring-using-a-novel-split-nanoluc-nanobit
#10
Kentaro Oh-Hashi, Yoko Hirata, Kazutoshi Kiuchi
In the present study, we applied a highly sensitive NanoLuc-based technology to understand the status of superoxide dismutase 1 (SOD1) within mammalian cells. Two fragments of NanoLuc (NanoBit), large N-terminal and small C-terminal regions, were fused with wild-type (wt) and mutant human SOD1 (hSOD1) genes and transfected into cells. Luciferase activity through NanoBit assembly was only detected in NanoBit-tagged wtSOD1-expressing cells. Furthermore, the developed NanoLuc system was used to investigate the role of protein-protein interactions in the pathogenesis of amyotrophic lateral sclerosis (ALS)...
October 2016: Cell Biochemistry and Function
https://www.readbyqxmd.com/read/27452472/in%C3%A2-vivo-formation-of-vacuolated-multi-phase-compartments-lacking-membranes
#11
Hermann Broder Schmidt, Rajat Rohatgi
Eukaryotic cells contain membrane-less organelles, including nucleoli and stress granules, that behave like liquid droplets. Such endogenous condensates often have internal substructure, but how this is established in the absence of membrane encapsulation remains unclear. We find that the N- and C-terminal domains of TDP43, a heterogeneous nuclear ribonucleoprotein implicated in neurodegenerative diseases, are capable of driving the formation of sub-structured liquid droplets in vivo. These droplets contain dynamic internal "bubbles" of nucleoplasm, reminiscent of membrane-based multi-vesicular endosomes...
August 2, 2016: Cell Reports
https://www.readbyqxmd.com/read/27324898/protein-profile-and-morphological-alterations-in-penumbra-after-focal-photothrombotic-infarction-in-the-rat-cerebral-cortex
#12
Anatoly Uzdensky, Svetlana Demyanenko, Grigory Fedorenko, Tayana Lapteva, Alexej Fedorenko
After ischemic stroke, cell damage propagates from infarct core to surrounding tissues (penumbra). To reveal proteins involved in neurodegeneration and neuroprotection in penumbra, we studied protein expression changes in 2-mm ring around the core of photothrombotic infarct induced in the rat brain cortex by local laser irradiation after administration of Bengal Rose. The ultrastructural study showed edema and degeneration of neurons, glia, and capillaries. Morphological changes gradually decreased across the penumbra...
June 21, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27318192/post-translational-protein-arginylation-in-the-normal-nervous-system-and-in-neurodegeneration
#13
REVIEW
Mauricio R Galiano, Victor E Goitea, Marta E Hallak
Post-translational arginylation of proteins is an important regulator of many physiological pathways in cells. This modification was originally noted in protein degradation during neurodegenerative processes, with an apparently different physiological relevance between central and peripheral nervous system. Subsequent studies have identified a steadily increasing number of proteins and proteolysis-derived polypeptides as arginyltransferase (ATE1) substrates, including β-amyloid, α-synuclein, and TDP43 proteolytic fragments...
August 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27239528/discriminative-and-prognostic-potential-of-cerebrospinal-fluid-phosphotau-tau-ratio-and-neurofilaments-for-frontotemporal-dementia-subtypes
#14
Yolande A L Pijnenburg, Nicolaas A Verwey, Wiesje M van der Flier, Philip Scheltens, Charlotte E Teunissen
INTRODUCTION: A decreased cerebrospinal fluid (CSF) p-Tau181 to total tau ratio (p/t-tau) is a biomarker for frontotemporal lobar degeneration with TDP43 inclusions (FTLD-TDP) and for amyotrophic lateral sclerosis (ALS). CSF light chain neurofilaments (NfL) are increased in ALS. We examined whether CSF p/t-tau and NfL are related to ALS status in FTLD-TDP. METHODS: We compared CSF p/t-tau and NfL levels between patients with FTLD-TDP with ALS (n = 15), FTLD-TDP without ALS (n = 17), FTLD-Tau (n = 6), Alzheimer's disease (AD; n = 25), and subjective memory complaints (SMC, n = 24)...
December 2015: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
https://www.readbyqxmd.com/read/27229480/proteomic-analysis-of-novel-targets-associated-with-the-enhancement-of-trka-induced-sk-n-mc-cancer-cell-death-caused-by-ngf
#15
Eun Joo Jung, Ky Hyun Chung, Dong-Won Bae, Choong Won Kim
Nerve growth factor (NGF) is known to regulate both cancer cell survival and death signaling, depending on the cellular circumstances, in various cell types. In this study, we showed that NGF strongly upregulated the protein level of tropomyosin-related kinase A (TrkA) in TrkA-inducible SK-N-MC cancer cells, resulting in increases in various TrkA-dependent cellular processes, including the phosphorylation of c-Jun N-terminal kinase (JNK) and caspase-8 cleavage. In addition, NGF enhanced TrkA-induced morphological changes and cell death, and this effect was significantly suppressed by the JNK inhibitor SP600125, but not by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin...
2016: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/27150074/oxidative-stress-and-mitochondrial-damage-in-the-pathogenesis-of-als-new-perspectives
#16
REVIEW
F Bozzo, A Mirra, M T Carrì
This review attempts to reconcile the present dual view of the mechanisms operating in Amyotrophic Lateral Sclerosis (ALS). On one side, oxidative stress, mitochondrial damage and protein aggregation are considered as causative of the disease, as strongly supported by evidence obtained in models based on the expression of ALS-typical mutant SOD1. On the other hand, evidence from models expressing ALS-typical mutations in RNA-binding proteins such as FUS and TDP43 indicate that mRNA (dys)metabolism is a major pathway in this disease...
January 1, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/27110240/structural-dynamics-of-human-argonaute2-and-its-interaction-with-sirnas-designed-to-target-mutant-tdp43
#17
Vishwambhar Bhandare, Amutha Ramaswamy
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 flexible region...
2016: Advances in Bioinformatics
https://www.readbyqxmd.com/read/26979082/altered-proteins-in-the-aging-brain
#18
Adila Elobeid, Sylwia Libard, Marina Leino, Svetlana N Popova, Irina Alafuzoff
We assessed the prevalence of common altered brain proteins in 296 cognitively unimpaired subjects ranging from age 50 to 102 years. The incidence and the stage of hyperphosphorylated-τ (HPτ), β-amyloid, α-synuclein (αS), and transactive response DNA (TDP) binding protein 43 (TDP43)-immunoreactivity (-IR) increased with age. HPτ-IR was observed in 98% of the subjects; the locus coeruleus was solely affected in 46%, and 79% of the subjects were in Braak stages a to II. β-Amyloid was seen in 47% of subjects and the Thal phase correlated with the HPτ Braak stage and age...
April 2016: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/26902425/high-tdp43-expression-is-required-for-trim16-induced-inhibition-of-cancer-cell-growth-and-correlated-with-good-prognosis-of-neuroblastoma-and-breast-cancer-patients
#19
Patrick Y Kim, Owen Tan, Bing Liu, Toby Trahair, Tao Liu, Michelle Haber, Murray D Norris, Glenn M Marshall, Belamy B Cheung
Tripartite Motif-containing protein 16 (TRIM16) is a member of a large family of tripartite motif (TRIM) proteins, that has been implicated in the pathogenesis of multiple cancers. However, the mechanism by which TRIM16 acts as a tumour suppressor is currently unknown. We used the versatile yeast two-hybrid assay on a cDNA library from human testes, which has relative high TRIM16 expression, to identify potential TRIM16-binding proteins. We identified transactive response DNA-binding protein 43 (TDP43) as a novel TRIM16 binding protein...
May 1, 2016: Cancer Letters
https://www.readbyqxmd.com/read/26854610/identification-of-possible-sirna-molecules-for-tdp43-mutants-causing-amyotrophic-lateral-sclerosis-in-silico-design-and-molecular-dynamics-study
#20
Vishwambhar Vishnu Bhandare, Amutha Ramaswamy
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, (iii) determination of the ability of siRNA to interact with mRNA and the formation/stability of duplex via molecular dynamics study for a period of 15ns and (iv) characterization of mRNA-siRNA duplex stability based on thermo-physical analysis...
April 2016: Computational Biology and Chemistry
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