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https://www.readbyqxmd.com/read/29860311/pak1-regulates-atxn1-levels-providing-an-opportunity-to-modify-its-toxicity-in-spinocerebellar-ataxia-type-1
#1
Vitaliy V Bondar, Carolyn J Adamski, Tarik S Onur, Qiumin Tan, Li Wang, Javier Diaz-Garcia, Jeehye Park, Harry T Orr, Juan Botas, Huda Y Zoghbi
Spinocerebellar ataxia type 1 (SCA1) is caused by the expansion of a trinucleotide repeat that encodes a polyglutamine tract in ataxin-1 (ATXN1). The expanded polygultamine in ATXN1 increases the protein's stability and results in its accumulation and toxicity. Previous studies have demonstrated that decreasing ATXN1 levels ameliorates SCA1 phenotypes and pathology in mouse models. We rationalized that reducing ATXN1 levels through pharmacological inhibition of its modulators could provide a therapeutic avenue for SCA1...
May 30, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29852174/dual-specificity-phosphatase-18-modulates-the-sumoylation-and-aggregation-of-ataxin-1
#2
Joohyun Ryu, Do Hee Lee
We previously reported that SUMOylation promotes the aggregation of ataxin-1 and JNK is involved in the process. Here we show that dual-specificity phosphatase 18 (DUSP18), a member of protein tyrosine phosphatases, exerts the opposite effects on ataxin-1. DUSP18 associated with ataxin-1 and suppressed JNK activated by ataxin-1. Interestingly DUSP18, but not the other DUSPs interacting with ataxin-1, caused the mobility shift of ataxin-1. De-phosphorylation by DUSP18 was initially suspected as a cause for such an effect; however, the phosphorylation of ataxin-1 was unchanged...
May 28, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29758256/reduction-of-protein-kinase-a-mediated-phosphorylation-of-atxn1-s776-in-purkinje-cells-delays-onset-of-ataxia-in-a-sca1-mouse-model
#3
Judit M Pérez Ortiz, Nissa Mollema, Nicholas Toker, Carolyn J Adamski, Brennon O'Callaghan, Lisa Duvick, Jillian Friedrich, Michael A Walters, Jessica Strasser, Jon E Hawkinson, Huda Y Zoghbi, Christine Henzler, Harry T Orr, Sarita Lagalwar
Spinocerebellar ataxia type 1 (SCA1) is a polyglutamine (polyQ) repeat neurodegenerative disease in which a primary site of pathogenesis are cerebellar Purkinje cells. In addition to polyQ expansion of ataxin-1 protein (ATXN1), phosphorylation of ATXN1 at the serine 776 residue (ATXN1-pS776) plays a significant role in protein toxicity. Utilizing a biochemical approach, pharmacological agents and cell-based assays, including SCA1 patient iPSC-derived neurons, we examine the role of Protein Kinase A (PKA) as an effector of ATXN1-S776 phosphorylation...
May 11, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29526553/atxn1-cic-complex-is-the-primary-driver-of-cerebellar-pathology-in-spinocerebellar-ataxia-type-1-through-a-gain-of-function-mechanism
#4
Maxime W C Rousseaux, Tyler Tschumperlin, Hsiang-Chih Lu, Elizabeth P Lackey, Vitaliy V Bondar, Ying-Wooi Wan, Qiumin Tan, Carolyn J Adamski, Jillian Friedrich, Kirk Twaroski, Weili Chen, Jakub Tolar, Christine Henzler, Ajay Sharma, Aleksandar Bajić, Tao Lin, Lisa Duvick, Zhandong Liu, Roy V Sillitoe, Huda Y Zoghbi, Harry T Orr
Polyglutamine (polyQ) diseases are caused by expansion of translated CAG repeats in distinct genes leading to altered protein function. In spinocerebellar ataxia type 1 (SCA1), a gain of function of polyQ-expanded ataxin-1 (ATXN1) contributes to cerebellar pathology. The extent to which cerebellar toxicity depends on its cognate partner capicua (CIC), versus other interactors, remains unclear. It is also not established whether loss of the ATXN1-CIC complex in the cerebellum contributes to disease pathogenesis...
March 21, 2018: Neuron
https://www.readbyqxmd.com/read/29401430/destabilizing-the-axh-tetramer-by-mutations-mechanisms-and-potential-antiaggregation-strategies
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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