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ataxin-1

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https://www.readbyqxmd.com/read/29401430/destabilizing-the-axh-tetramer-by-mutations-mechanisms-and-potential-antiaggregation-strategies
#1
Gianvito Grasso, Umberto Morbiducci, Diana Massai, Jack A Tuszynski, Andrea Danani, Marco A Deriu
The AXH domain of protein Ataxin 1 is thought to play a key role in the misfolding and aggregation pathway responsible for Spinocerebellar ataxia 1. For this reason, a molecular level understanding of AXH oligomerization pathway is crucial to elucidate the aggregation mechanism, which is thought to trigger the disease. This study employs classical and enhanced molecular dynamics to identify the structural and energetic basis of AXH tetramer stability. Results of this work elucidate molecular mechanisms behind the destabilizing effect of protein mutations, which consequently affect the AXH tetramer assembly...
January 23, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/29212253/ataxin-1-is-involved-in-tumorigenesis-of-cervical-cancer-cells-via-the-egfr-ras-mapk-signaling-pathway
#2
A-Ram Kang, Hyoung-Tae An, Jesang Ko, Eui-Ju Choi, Seongman Kang
Ataxin-1 (ATXN1) is a coregulator protein within which expansion of the polyglutamine tract causes spinocerebellar ataxia type 1, an autosomal dominant neurodegenerative disorder. Previously, we reported that ATXN1 regulates the epithelial-mesenchymal transition of cervical cancer cells. In the present study, we demonstrate that ATXN1 is involved in cervical cancer tumorigenesis by promoting the proliferation of human cervical cancer cells. Chromatin immunoprecipitation assays showed that ATXN1 bound to the promoter region within cyclin D1 and activated cyclin D1 transcription, resulting in cell proliferation...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29211771/short-term-succinic-acid-treatment-mitigates-cerebellar-mitochondrial-oxphos-dysfunction-neurodegeneration-and-ataxia-in-a-purkinje-specific-spinocerebellar-ataxia-type-1-sca1-mouse-model
#3
Austin Ferro, Emily Carbone, Jenny Zhang, Evan Marzouk, Monica Villegas, Asher Siegel, Donna Nguyen, Thomas Possidente, Jessilyn Hartman, Kailen Polley, Melissa A Ingram, Georgia Berry, Thomas H Reynolds, Bernard Possidente, Kimberley Frederick, Stephen Ives, Sarita Lagalwar
Mitochondrial dysfunction plays a significant role in neurodegenerative disease including ataxias and other movement disorders, particularly those marked by progressive degeneration in the cerebellum. In this study, we investigate the role of mitochondrial oxidative phosphorylation (OXPHOS) deficits in cerebellar tissue of a Purkinje cell-driven spinocerebellar ataxia type 1 (SCA1) mouse. Using RNA sequencing transcriptomics, OXPHOS complex assembly analysis and oxygen consumption assays, we report that in the presence of mutant polyglutamine-expanded ataxin-1, SCA1 mice display deficits in cerebellar OXPHOS complex I (NADH-coenzyme Q oxidoreductase)...
2017: PloS One
https://www.readbyqxmd.com/read/29192206/developmental-yapdeltac-determines-adult-pathology-in-a-model-of-spinocerebellar-ataxia-type-1
#4
Kyota Fujita, Ying Mao, Shigenori Uchida, Xigui Chen, Hiroki Shiwaku, Takuya Tamura, Hikaru Ito, Kei Watase, Hidenori Homma, Kazuhiko Tagawa, Marius Sudol, Hitoshi Okazawa
YAP and its neuronal isoform YAPdeltaC are implicated in various cellular functions. We found that expression of YAPdeltaC during development, but not adulthood, rescued neurodegeneration phenotypes of mutant ataxin-1 knock-in (Atxn1-KI) mice. YAP/YAPdeltaC interacted with RORα via the second WW domain and served as co-activators of its transcriptional activity. YAP/YAPdeltaC formed a transcriptional complex with RORα on cis-elements of target genes and regulated their expression. Both normal and mutant Atxn1 interacted with YAP/YAPdeltaC, but only mutant Atxn1 depleted YAP/YAPdeltaC from the RORα complex to suppress transcription on short timescales...
November 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/28545543/inhibition-of-colony-stimulating-factor-1-receptor-early-in-disease-ameliorates-motor-deficits-in-sca1-mice
#5
Wenhui Qu, Andrea Johnson, Joo Hyun Kim, Abigail Lukowicz, Daniel Svedberg, Marija Cvetanovic
BACKGROUND: Polyglutamine (polyQ) expansion in the protein Ataxin-1 (ATXN1) causes spinocerebellar ataxia type 1 (SCA1), a fatal dominantly inherited neurodegenerative disease characterized by motor deficits, cerebellar neurodegeneration, and gliosis. Currently, there are no treatments available to delay or ameliorate SCA1. We have examined the effect of depleting microglia during the early stage of disease by using PLX, an inhibitor of colony-stimulating factor 1 receptor (CSFR1), on disease severity in a mouse model of SCA1...
May 25, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28288114/disruption-of-the-atxn1-cic-complex-causes-a-spectrum-of-neurobehavioral-phenotypes-in-mice-and-humans
#6
Hsiang-Chih Lu, Qiumin Tan, Maxime W C Rousseaux, Wei Wang, Ji-Yoen Kim, Ronald Richman, Ying-Wooi Wan, Szu-Ying Yeh, Jay M Patel, Xiuyun Liu, Tao Lin, Yoontae Lee, John D Fryer, Jing Han, Maria Chahrour, Richard H Finnell, Yunping Lei, Maria E Zurita-Jimenez, Priyanka Ahimaz, Kwame Anyane-Yeboa, Lionel Van Maldergem, Daphne Lehalle, Nolwenn Jean-Marcais, Anne-Laure Mosca-Boidron, Julien Thevenon, Margot A Cousin, Della E Bro, Brendan C Lanpher, Eric W Klee, Nora Alexander, Matthew N Bainbridge, Harry T Orr, Roy V Sillitoe, M Cecilia Ljungberg, Zhandong Liu, Christian P Schaaf, Huda Y Zoghbi
Gain-of-function mutations in some genes underlie neurodegenerative conditions, whereas loss-of-function mutations in the same genes have distinct phenotypes. This appears to be the case with the protein ataxin 1 (ATXN1), which forms a transcriptional repressor complex with capicua (CIC). Gain of function of the complex leads to neurodegeneration, but ATXN1-CIC is also essential for survival. We set out to understand the functions of the ATXN1-CIC complex in the developing forebrain and found that losing this complex results in hyperactivity, impaired learning and memory, and abnormal maturation and maintenance of upper-layer cortical neurons...
April 2017: Nature Genetics
https://www.readbyqxmd.com/read/28212558/ataxin-1-regulates-epithelial-mesenchymal-transition-of-cervical-cancer-cells
#7
A-Ram Kang, Hyoung-Tae An, Jesang Ko, Seongman Kang
The mutant form of the protein ataxin-1 (ATXN1) causes the neurodegenerative disease spinocerebellar ataxia type-1. Recently, ATXN1 was reported to enhance E-cadherin expression in the breast cancer cell line MCF-7, suggesting a potential association between ATXN1 and cancer development. In the present study, we discovered a novel mechanism through which ATXN1 regulates the epithelial-mesenchymal transition (EMT) of cancer cells. Hypoxia-induced upregulation of the Notch intracellular domain expression decreased ATXN1 expression via MDM2-associated ubiquitination and degradation...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28173122/rpa1-ameliorates-symptoms-of-mutant-ataxin-1-knock-in-mice-and-enhances-dna-damage-repair
#8
Juliana Bosso Taniguchi, Kanoh Kondo, Kyota Fujita, Xigui Chen, Hidenori Homma, Takeaki Sudo, Ying Mao, Kei Watase, Toshihiro Tanaka, Kazuhiko Tagawa, Takuya Tamura, Shin-Ichi Muramatsu, Hitoshi Okazawa
DNA damage and repair is a critical domain of many neurodegenerative diseases. In this study, we focused on RpA1, a candidate key molecule in polyQ disease pathologies, and tested the therapeutic effect of adeno-associated virus (AAV) vector expressing RpA1 on mutant Ataxin-1 knock-in (Atxn1-KI) mice. We found significant effects on motor functions, normalized DNA damage markers (γH2AX and 53BP1), and improved Purkinje cell morphology; effects that lasted for 50 weeks following AAV-RpA1 infection. In addition, we confirmed that AAV-RpA1 indirectly recovered multiple cellular functions such as RNA splicing, transcription and cell cycle as well as abnormal morphology of dendrite and dendritic spine of Purkinje cells in Atxn1-KI mice...
October 15, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27895927/expansion-mosaicism-and-interruption-mechanisms-of-the-cag-repeat-mutation-in-spinocerebellar-ataxia-type-1
#9
REVIEW
Cara Kraus-Perrotta, Sarita Lagalwar
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that primarily affects the cerebellum and brainstem. The genetic mutation is an expansion of CAG trinucleotide repeats within the coding region of the ataxin-1 gene, characterizing SCA1 as a polyglutamine expansion disease like Huntington's. As with most polyglutamine expansion diseases, SCA1 follows the rules of genetic anticipation: the larger the expansion, the earlier and more rapid the symptoms. Unlike the majority of polyglutamine expansion diseases, the presence of histidine interruptions within the polyglutamine tract of ataxin-1 protein can prevent or mitigate disease...
2016: Cerebellum & Ataxias
https://www.readbyqxmd.com/read/27686464/rnai-prevents-and-reverses-phenotypes-induced-by-mutant-human-ataxin-1
#10
Megan S Keiser, Alejandro Mas Monteys, Romuald Corbau, Pedro Gonzalez-Alegre, Beverly L Davidson
OBJECTIVE: Spinocerebellar ataxia type 1 is an autosomal dominant fatal neurodegenerative disease caused by a polyglutamine expansion in the coding region of ATXN1. We showed previously that partial suppression of mutant ataxin-1 (ATXN1) expression, using virally expressed RNAi triggers, could prevent disease symptoms in a transgenic mouse model and a knockin mouse model of the disease, using a single dose of virus. Here, we set out to test whether RNAi triggers targeting ATXN1 could not only prevent, but also reverse disease readouts when delivered after symptom onset...
November 2016: Annals of Neurology
https://www.readbyqxmd.com/read/27684355/assays-for-the-degradation-of-misfolded-proteins-in-cells
#11
Lili Guo, Wil Prall, Xiaolu Yang
Protein misfolding and aggregation are associated with various neurodegenerative diseases. Cellular mechanisms that recognize and degrade misfolded proteins may serve as potential therapeutic targets. To distinguish degradation of misfolding-prone proteins from other mechanisms that regulate their levels, one important method is to measure protein half-life in cells. However, this can be challenging because misfolding-prone proteins may exist in different forms, including the native form and misfolded forms of distinct characteristics...
August 28, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/27570504/gene-stem-cell-and-alternative-therapies-for-sca-1
#12
REVIEW
Jacob L Wagner, Deirdre M O'Connor, Anthony Donsante, Nicholas M Boulis
Spinocerebellar ataxia 1 is an autosomal dominant disease characterized by neurodegeneration and motor dysfunction. In disease pathogenesis, polyglutamine expansion within Ataxin-1, a gene involved in transcriptional repression, causes protein nuclear inclusions to form. Most notably, neuronal dysfunction presents in Purkinje cells. However, the effect of mutant Ataxin-1 is not entirely understood. Two mouse models are employed to represent spinocerebellar ataxia 1, a B05 transgenic model that specifically expresses mutant Ataxin-1 in Purkinje cells, and a Sca1 154Q/2Q model that inserts the polyglutamine expansion into the mouse Ataxin-1 locus so that the mutant Ataxin-1 is expressed in all cells that express Ataxin-1...
2016: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/27516390/rpa1-ameliorates-symptoms-of-mutant-ataxin-1-knock-in-mice-and-enhances-dna-damage-repair
#13
Juliana Bosso Taniguchi, Kanoh Kondo, Kyota Fujita, Xigui Chen, Hidenori Homma, Takeaki Sudo, Ying Mao, Kei Watase, Toshihiro Tanaka, Kazuhiko Tagawa, Takuya Tamura, Shin-Ichi Muramatsu, Hitoshi Okazawa
DNA damage and repair is a critical domain of many neurodegenerative diseases. In this study, we focused on RpA1, a candidate key molecule in polyQ disease pathologies, and tested the therapeutic effect of adeno-associated virus (AAV) vector expressing RpA1 on mutant Ataxin-1 knock-in (Atxn1-KI) mice. We found significant effects on motor functions, normalized DNA damage markers (γH2AX and 53BP1), and improved Purkinje cell morphology; effects that lasted for 50 weeks following AAV-RpA1 infection. In addition, we confirmed that AAV-RpA1 indirectly recovered multiple cellular functions such as RNA splicing, transcription and cell cycle as well as abnormal morphology of dendrite and dendritic spine of Purkinje cells in Atxn1-KI mice...
August 11, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27466200/ataxin-1-regulates-the-cerebellar-bioenergetics-proteome-through-the-gsk3%C3%AE-mtor-pathway-which-is-altered-in-spinocerebellar-ataxia-type-1-sca1
#14
Ivelisse Sánchez, Eudald Balagué, Antoni Matilla-Dueñas
A polyglutamine expansion within the ataxin-1 protein (ATXN1) underlies spinocerebellar ataxia type-1 (SCA1), a neurological disorder mainly characterized by ataxia and cerebellar deficits. In SCA1, both loss and gain of ATXN1 biological functions contribute to cerebellar pathogenesis. However, the critical ATXN1 functions and pathways involved remain unclear. To further investigate the early signalling pathways regulated by ATXN1, we performed an unbiased proteomic study of the Atxn1-KO 5-week-old mice cerebellum...
September 15, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27428326/proteasome-inhibition-contributed-to-the-cytotoxicity-of-arenobufagin-after-its-binding-with-na-k-atpase-in-human-cervical-carcinoma-hela-cells
#15
Qingxi Yue, Hong Zhen, Ming Huang, Xi Zheng, Lixing Feng, Baohong Jiang, Min Yang, Wanying Wu, Xuan Liu, Dean Guo
Although the possibility of developing cardiac steroids/cardiac glycosides as novel cancer therapeutic agents has been recognized, the mechanism of their anticancer activity is still not clear enough. Toad venom extract containing bufadienolides, which belong to cardiac steroids, has actually long been used as traditional Chinese medicine in clinic for cancer therapy in China. The cytotoxicity of arenobufagin, a bufadienolide isolated from toad venom, on human cervical carcinoma HeLa cells was checked. And, the protein expression profile of control HeLa cells and HeLa cells treated with arenobufagin for 48 h was analyzed using two-dimensional electrophoresis, respectively...
2016: PloS One
https://www.readbyqxmd.com/read/27394174/mitochondrial-impairments-contribute-to-spinocerebellar-ataxia-type-1-progression-and-can-be-ameliorated-by-the-mitochondria-targeted-antioxidant-mitoq
#16
David M Stucki, Céline Ruegsegger, Silvio Steiner, Julika Radecke, Michael P Murphy, Benoît Zuber, Smita Saxena
Spinocerebellar ataxia type 1 (SCA1), due to an unstable polyglutamine expansion within the ubiquitously expressed Ataxin-1 protein, leads to the premature degeneration of Purkinje cells (PCs), decreasing motor coordination and causing death within 10-15 years of diagnosis. Currently, there are no therapies available to slow down disease progression. As secondary cellular impairments contributing to SCA1 progression are poorly understood, here, we focused on identifying those processes by performing a PC specific proteome profiling of Sca1(154Q/2Q) mice at a symptomatic stage...
August 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27306906/mutant-ataxin-1-inhibits-neural-progenitor-cell-proliferation-in-sca1
#17
Marija Cvetanovic, Yuan-Shih Hu, Puneet Opal
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by the expansion of a polyglutamine (Q) repeat tract in the protein ataxin-1 (ATXN1). Beginning as a cerebellar ataxic disorder, SCA1 progresses to involve the cerebral cortex, hippocampus, and brainstem. Using SCA1 knock-in mice that mirror the complexity of the human disease, we report a significant decrease in the capacity of adult neuronal progenitor cells (NPCs) to proliferate. Remarkably, a decrease in NPCs proliferation can be observed in vitro, outside the degenerative milieu of surrounding neurons or glia, demonstrating that mutant ATXN1 acting cell autonomously within progenitor cells interferes with their ability to proliferate...
April 2017: Cerebellum
https://www.readbyqxmd.com/read/27140210/morphological-and-functional-attenuation-of-degeneration-of-peripheral-neurons-by-mesenchymal-stem-cell-conditioned-medium-in-spinocerebellar-ataxia-type-1-knock-in-mice
#18
Nana Suto, Tokue Mieda, Akira Iizuka, Kazuhiro Nakamura, Hirokazu Hirai
AIMS: Spinocerebellar ataxia type 1 (SCA1) is caused by the ataxin-1 protein (ATXN1) with an abnormally expanded polyglutamine tract and is characterized by progressive neurodegeneration. We previously showed that intrathecal injection of mesenchymal stem cells (MSCs) during the nonsymptomatic stage mitigates the degeneration of the peripheral nervous system (PNS) neurons in SCA1-knock-in (SCA1-KI) mice. We tested in this study whether the therapeutic effects of MSCs in SCA1-KI mice could be reproduced with MSC-releasing factor(s)...
August 2016: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/27058144/biib021-a-synthetic-hsp90-inhibitor-induces-mutant-ataxin-1-degradation-through-the-activation-of-heat-shock-factor-1
#19
Ying Ding, Hiroaki Adachi, Masahisa Katsuno, Kentaro Sahashi, Naohide Kondo, Madoka Iida, Genki Tohnai, Hideaki Nakatsuji, Gen Sobue
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by the expansion of a polyglutamine (polyQ) tract in ataxin-1 (ATXN1). The pathological hallmarks of SCA1 are the loss of cerebellar Purkinje cells and neurons in the brainstem and the presence of nuclear aggregates containing the polyQ-expanded ATXN1 protein. Heat shock protein 90 (Hsp90) inhibitors have been shown to reduce polyQ-induced toxicity. This study was designed to examine the therapeutic effects of BIIB021, a purine-scaffold Hsp90 inhibitor, on the protein homeostasis of polyQ-expanded mutant ATXN1 in a cell culture model of SCA1...
July 7, 2016: Neuroscience
https://www.readbyqxmd.com/read/26996412/prion-like-domains-as-epigenetic-regulators-scaffolds-for-subcellular-organization-and-drivers-of-neurodegenerative-disease
#20
REVIEW
Zachary M March, Oliver D King, James Shorter
Key challenges faced by all cells include how to spatiotemporally organize complex biochemistry and how to respond to environmental fluctuations. The budding yeast Saccharomyces cerevisiae harnesses alternative protein folding mediated by yeast prion domains (PrDs) for rapid evolution of new traits in response to environmental stress. Increasingly, it is appreciated that low complexity domains similar in amino acid composition to yeast PrDs (prion-like domains; PrLDs) found in metazoa have a prominent role in subcellular cytoplasmic organization, especially in relation to RNA homeostasis...
September 15, 2016: Brain Research
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