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Kanako Ono - One of the best experts on this subject based on the ideXlab platform.
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two caenorhabditis elegans calponin related proteins have overlapping functions that maintain Cytoskeletal integrity and are essential for reproduction
Journal of Biological Chemistry, 2020Co-Authors: Shoichiro Ono, Kanako OnoAbstract:Multicellular organisms have multiple genes encoding calponins and calponin-related proteins, some of which are known to regulate actin Cytoskeletal dynamics and contractility. However, the functional similarities and differences among these proteins are largely unknown. In the nematode Caenorhabditis elegans, UNC-87 is a calponin-related protein with seven calponin-like (CLIK) motifs and is required for maintenance of contractile apparatuses in muscle cells. Here, we report that CLIK-1, another calponin-related protein that also contains seven CLIK motifs, functionally overlaps with UNC-87 in maintaining actin Cytoskeletal integrity in vivo and has both common and different actin-regulatory activities in vitro. We found that CLIK-1 is predominantly expressed in the body wall muscle and somatic gonad in which UNC-87 is also expressed. unc-87 mutation caused Cytoskeletal Defects in the body wall muscle and somatic gonad, whereas clik-1 depletion alone caused no detectable phenotypes. However, simultaneous clik-1 and unc-87 depletion caused sterility because of ovulation failure by severely affecting the contractile actin networks in the myoepithelial sheath of the somatic gonad. In vitro, UNC-87 bundled actin filaments, whereas CLIK-1 bound to actin filaments without bundling them and antagonized UNC-87–mediated filament bundling. We noticed that UNC-87 and CLIK-1 share common functions that inhibit cofilin binding and allow tropomyosin binding to actin filaments, suggesting that both proteins stabilize actin filaments. In conclusion, partially redundant functions of UNC-87 and CLIK-1 in ovulation are likely mediated by their common actin-regulatory activities, but their distinct actin-bundling activities suggest that they also have different biological functions.
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two caenorhabditis elegans calponin related proteins have overlapping functions that maintain Cytoskeletal integrity and are essential for reproduction
Journal of Biological Chemistry, 2020Co-Authors: Shoichiro Ono, Kanako OnoAbstract:Multicellular organisms have multiple genes encoding calponins and calponin-related proteins, some of which are known to regulate actin Cytoskeletal dynamics and contractility. However, the functional similarities and differences among these proteins are largely unknown. In the nematode Caenorhabditis elegans, UNC-87 is a calponin-related protein with seven calponin-like (CLIK) motifs and is required for maintenance of contractile apparatuses in muscle cells. Here, we report that CLIK-1, another calponin-related protein that also contains seven CLIK motifs, functionally overlaps with UNC-87 in maintaining actin Cytoskeletal integrity in vivo and has both common and different actin-regulatory activities in vitro We found that CLIK-1 is predominantly expressed in the body wall muscle and somatic gonad where UNC-87 is also expressed. unc-87 mutation caused Cytoskeletal Defects in the body wall muscle and somatic gonad, whereas clik-1 depletion alone caused no detectable phenotypes. However, simultaneous clik-1 and unc-87 depletion caused sterility due to ovulation failure by severely affecting the contractile actin networks in the myoepithelial sheath of the somatic gonad. In vitro, UNC-87 bundled actin filaments, whereas CLIK-1 bound to actin filaments without bundling them and antagonized UNC-87-mediated filament bundling. We noticed that UNC-87 and CLIK-1 share common functions that inhibit cofilin binding and allow tropomyosin binding to actin filaments, suggesting that both proteins stabilize actin filaments. In conclusion, partially redundant functions of UNC-87 and CLIK-1 in ovulation are likely mediated by their common actin-regulatory activities, but their distinct actin-bundling activities suggest that they also have different biological functions.
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two caenorhabditis elegans calponin related proteins have overlapping functions to maintain Cytoskeletal integrity and are essential for reproduction
bioRxiv, 2020Co-Authors: Shoichiro Ono, Kanako OnoAbstract:Multicellular organisms have multiple genes encoding calponins and calponin-related proteins, and some of these are known to regulate actin Cytoskeletal dynamics and contractility. However, functional similarities and differences among these proteins are largely unknown. In the nematode Caenorhabditis elegans, UNC-87 is a calponin-related protein with seven calponin-like (CLIK) motifs and is required for maintenance of contractile apparatuses in muscle cells. Here, we report that CLIK-1, another calponin-related protein that also contains seven CLIK motifs, has an overlapping function with UNC-87 to maintain actin Cytoskeletal integrity in vivo and has both common and different actin-regulatory activities in vitro. CLIK-1 is predominantly expressed in the body wall muscle and somatic gonad, where UNC-87 is also expressed. unc-87 mutation causes Cytoskeletal Defects in the body wall muscle and somatic gonad, whereas clik-1 depletion alone causes no detectable phenotypes. However, simultaneous depletion of clik-1 and unc-87 caused sterility due to ovulation failure by severely affecting the contractile actin networks in the myoepithelial sheath of the somatic gonad. In vitro, UNC-87 bundles actin filaments. However, CLIK-1 binds to actin filaments without bundling them and is antagonistic to UNC-87 in filament bundling. UNC-87 and CLIK-1 share common functions to inhibit cofilin binding and allow tropomyosin binding to actin filaments, suggesting that both proteins stabilize actin filaments. Thus, partially redundant functions of UNC-87 and CLIK-1 in ovulation is likely mediated by their common actin-regulatory activities, but their distinct activities in actin bundling suggest that they also have different biological functions.
Shoichiro Ono - One of the best experts on this subject based on the ideXlab platform.
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two caenorhabditis elegans calponin related proteins have overlapping functions that maintain Cytoskeletal integrity and are essential for reproduction
Journal of Biological Chemistry, 2020Co-Authors: Shoichiro Ono, Kanako OnoAbstract:Multicellular organisms have multiple genes encoding calponins and calponin-related proteins, some of which are known to regulate actin Cytoskeletal dynamics and contractility. However, the functional similarities and differences among these proteins are largely unknown. In the nematode Caenorhabditis elegans, UNC-87 is a calponin-related protein with seven calponin-like (CLIK) motifs and is required for maintenance of contractile apparatuses in muscle cells. Here, we report that CLIK-1, another calponin-related protein that also contains seven CLIK motifs, functionally overlaps with UNC-87 in maintaining actin Cytoskeletal integrity in vivo and has both common and different actin-regulatory activities in vitro. We found that CLIK-1 is predominantly expressed in the body wall muscle and somatic gonad in which UNC-87 is also expressed. unc-87 mutation caused Cytoskeletal Defects in the body wall muscle and somatic gonad, whereas clik-1 depletion alone caused no detectable phenotypes. However, simultaneous clik-1 and unc-87 depletion caused sterility because of ovulation failure by severely affecting the contractile actin networks in the myoepithelial sheath of the somatic gonad. In vitro, UNC-87 bundled actin filaments, whereas CLIK-1 bound to actin filaments without bundling them and antagonized UNC-87–mediated filament bundling. We noticed that UNC-87 and CLIK-1 share common functions that inhibit cofilin binding and allow tropomyosin binding to actin filaments, suggesting that both proteins stabilize actin filaments. In conclusion, partially redundant functions of UNC-87 and CLIK-1 in ovulation are likely mediated by their common actin-regulatory activities, but their distinct actin-bundling activities suggest that they also have different biological functions.
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two caenorhabditis elegans calponin related proteins have overlapping functions that maintain Cytoskeletal integrity and are essential for reproduction
Journal of Biological Chemistry, 2020Co-Authors: Shoichiro Ono, Kanako OnoAbstract:Multicellular organisms have multiple genes encoding calponins and calponin-related proteins, some of which are known to regulate actin Cytoskeletal dynamics and contractility. However, the functional similarities and differences among these proteins are largely unknown. In the nematode Caenorhabditis elegans, UNC-87 is a calponin-related protein with seven calponin-like (CLIK) motifs and is required for maintenance of contractile apparatuses in muscle cells. Here, we report that CLIK-1, another calponin-related protein that also contains seven CLIK motifs, functionally overlaps with UNC-87 in maintaining actin Cytoskeletal integrity in vivo and has both common and different actin-regulatory activities in vitro We found that CLIK-1 is predominantly expressed in the body wall muscle and somatic gonad where UNC-87 is also expressed. unc-87 mutation caused Cytoskeletal Defects in the body wall muscle and somatic gonad, whereas clik-1 depletion alone caused no detectable phenotypes. However, simultaneous clik-1 and unc-87 depletion caused sterility due to ovulation failure by severely affecting the contractile actin networks in the myoepithelial sheath of the somatic gonad. In vitro, UNC-87 bundled actin filaments, whereas CLIK-1 bound to actin filaments without bundling them and antagonized UNC-87-mediated filament bundling. We noticed that UNC-87 and CLIK-1 share common functions that inhibit cofilin binding and allow tropomyosin binding to actin filaments, suggesting that both proteins stabilize actin filaments. In conclusion, partially redundant functions of UNC-87 and CLIK-1 in ovulation are likely mediated by their common actin-regulatory activities, but their distinct actin-bundling activities suggest that they also have different biological functions.
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two caenorhabditis elegans calponin related proteins have overlapping functions to maintain Cytoskeletal integrity and are essential for reproduction
bioRxiv, 2020Co-Authors: Shoichiro Ono, Kanako OnoAbstract:Multicellular organisms have multiple genes encoding calponins and calponin-related proteins, and some of these are known to regulate actin Cytoskeletal dynamics and contractility. However, functional similarities and differences among these proteins are largely unknown. In the nematode Caenorhabditis elegans, UNC-87 is a calponin-related protein with seven calponin-like (CLIK) motifs and is required for maintenance of contractile apparatuses in muscle cells. Here, we report that CLIK-1, another calponin-related protein that also contains seven CLIK motifs, has an overlapping function with UNC-87 to maintain actin Cytoskeletal integrity in vivo and has both common and different actin-regulatory activities in vitro. CLIK-1 is predominantly expressed in the body wall muscle and somatic gonad, where UNC-87 is also expressed. unc-87 mutation causes Cytoskeletal Defects in the body wall muscle and somatic gonad, whereas clik-1 depletion alone causes no detectable phenotypes. However, simultaneous depletion of clik-1 and unc-87 caused sterility due to ovulation failure by severely affecting the contractile actin networks in the myoepithelial sheath of the somatic gonad. In vitro, UNC-87 bundles actin filaments. However, CLIK-1 binds to actin filaments without bundling them and is antagonistic to UNC-87 in filament bundling. UNC-87 and CLIK-1 share common functions to inhibit cofilin binding and allow tropomyosin binding to actin filaments, suggesting that both proteins stabilize actin filaments. Thus, partially redundant functions of UNC-87 and CLIK-1 in ovulation is likely mediated by their common actin-regulatory activities, but their distinct activities in actin bundling suggest that they also have different biological functions.
Brendan Kenna - One of the best experts on this subject based on the ideXlab platform.
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genome wide analyses identify kif5a as a novel als gene
Neuron, 2018Co-Authors: Aude Nicolas, Kevin Kenna, Alan E Renton, Janice A. Dominov, Faraz Faghri, Nicola Ticozzi, R. Chia, Brendan KennaAbstract:To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of Cytoskeletal Defects in the pathogenesis of ALS.
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Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
'Elsevier BV', 2018Co-Authors: Nicolas A, Kevin Kenna, Brendan Kenna, Janice A. Dominov, Ae Renton, Ticozzi N, Faghri F, Chia R, Keagle PAbstract:To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of Cytoskeletal Defects in the pathogenesis of ALS.The ALS Association (ALSA) provided funding support to Project MinE (15-LGCA-235), the NYGC ALS Consortium (15-LGCA-234), the CReATe Consortium (17-LGCA-331), the GTAC Consortium (16-LGCA-310), the Target ALS Human Postmortem Tissue Core (16-LGCA-308), and NeuroLINCS, an NIH-funded collaborative effort. P.V.D. is a senior investigator of FWO-Vlaanderen. Project MinE Belgium has been supported by ALS liga België, Flanders Innovation & Enterpreneurship (IWT grant Project MinE), the Belgian National Lottery, and a grant from Opening the Future Fund (KU Leuven). W.R. is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders and ERC (grant agreement no. 340429). Additional funding support includes NINDS R35 NS097261 (R.R.) and P01NS084974 (R.R. and K.B.B.). A.N.B. thanks the Suna and Inan Kirac Foundation, Istanbul, TR for its generous support of the Neurodegeneration Research Laboratory throughout this study. Funding for this work was provided by the Heaton-Ellis Trust, the Middlemass Family, Motor Neurone Disease Association, Medical Research Council, Medical Research Foundation, the Psychiatry Research Trust of the Institute of Psychiatry, Guy's and St Thomas' Charity, the Wellcome Trust, and the Noreen Murray Foundation (C.E.S.). This work was also supported by the UK Dementia Research Institute, which is funded by the Medical Research Council, Alzheimer's Society, and Alzheimer’s Research UK (C.E.S.). The salary for B.N.S. was funded by the Medical Research Foundation (MRF) (MRF-060-0003-RG-SMITH). P.C.S. was supported through the auspices of Dr. H. Robert Horvitz (Massachusetts Institute of Technology), an Investigator of the Howard Hughes Institute. Support for this work came from the Department of Veterans Affairs and NIH (P30AG13846) to N.W.K. I.P.B. is supported by the Motor Neurone Disease Research Institute of Australia and the National Health and Medical Research Council of Australia (1107644 and 1095215). P.F. is supported by an MRC/MNDA LEWF and by NIHR UCLH BRC. Research support from NIH/NIEHS (K23ES027221), the ALS Association, Target ALS, and Cytokinetics was provided to S.A.G. M. Cudkowicz was awarded funding from ALS Finding a Cure. N.T., C. Tiloca, C.G., V.S., and J.E.L. received research support from AriSLA – Fondazione Italiana di Ricerca per la SLA (grants EXOMEFALS and NOVALS) and the Italian Ministry of Health (grant GR-2011-02347820 - IRisALS). R.L. McLaughlin was supported by Science Foundation Ireland and the MND Association of England, Wales and Northern Ireland. O.H. is funded by the Health Research Board Clinician Scientist Programme and Science Foundation Ireland. P.J.S. is supported as an NIHR Senior Investigator (NF-SI-0512-10082). P.J.S. and J. Kirby are supported by the Sheffield NIHR Biomedical Research Centre for Translational Neuroscience (IS-BRC-1215-20017). A. Chiò receives research support from the Italian Ministry of Health (Ricerca Finalizzata), Regione Piemonte (Ricerca Finalizzata), University of Turin, Fondazione Vialli e Mauro onlus, and the European Commission (Health Seventh Framework Programme). P.M.A. is supported by research grants from the Swedish Brain Foundation, the Swedish Science Council, the Knut and Alice Wallenberg Foundation, the Bertil Hållsten Foundation, the Ulla-Carin Lindquist Foundation, the Neuroförbundet Association, the Torsten and Ragnar Söderberg Foundation, the Stratneuro Initiative, and Västerbotten County Council. R.B. received funding support from NINDS/NS061867 and Target ALS. R.H.B.J. received funding from the Angel Fund, Project ALS/P2ALS, and the ALS Therapy Alliance. E. Rogaeva received funding support from the Canadian Consortium on Neurodegeneration in Aging. L. Myllykangas received funding support from Helsinki University Hospital and the Academy of Finland (grant 294817). P.T. received funding support from Helsinki University Hospital and the Sigrid Jusélius Foundation. J.D.G. received funding support from the ALS Association and Muscular Dystrophy Association. Additional funding was provided by the NIH/NINDS (R01NS073873, J.E.L.), the ALS Association (N.T., V.S., C.E.S., R.H.B.J., and J.E.L.), and the MND Association (N.T., V.S., C.E.S., and J.E.L.). J. Kaye, S.F., S.K.W., A.L., E.F., C.N.S., L.M.T., J.E.V.E., and J.D.R. received funding through NeuroLINCS (NIH U54 NS091046). The sequencing activities at NYGC were additionally supported by the TOW Foundation. The CReATe consortium (U54NS092091) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS. This consortium is funded through collaboration between NCATS and the NINDS. The Target ALS Human Postmortem Tissue Core received funding support from Target ALS (grant 90072272). The InCHIANTI study baseline (1998–2000) was supported as a “targeted project” (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the United States National Institute on Aging (contracts 263 MD 9164 and 263 MD 821336), the InCHIANTI follow-up 1 (2001–2003) was funded by the United States National Institute on Aging (contracts N.1-AG-1-1 and N.1-AG-1-2111), and the InCHIANTI follow-ups 2 and 3 studies (2004–2010) were financed by the United States National Institute on Aging (contract N01-AG-5-0002). This work was supported in part by the Intramural Research Programs of the NIH, National Institute on Aging (Z01-AG000949-02); by the National Institute of Neurological Disorders and Stroke; and by Merck & Co., Inc.. The work was also supported by the Center for Disease Control and Prevention, the Muscular Dystrophy Association, Microsoft Research, the Packard Center for ALS Research at Johns Hopkins, the ALS Association, UK MND Association, Medical Research Council (MRC) UK, Wellcome Trust/MRC Joint Call in Neurodegeneration Award, MRC Neuromuscular Centre, UK National Institute for Health Research Biomedical Research Unit, Italian Health Ministry (Ricerca Sanitaria Finalizzata 2007), Fondazione Vialli e Mauro Onlus, Compagnia di San Paolo, and European Community’s Health Seventh Framework Programme (FP7/2007-2013) under grant agreement 259867
Albert Galy - One of the best experts on this subject based on the ideXlab platform.
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A lentiviral vector encoding the human Wiskott-Aldrich syndrome protein corrects immune and Cytoskeletal Defects in WASP knockout mice.
Gene Ther, 2005Co-Authors: Albert GalyAbstract:Wiskott-Aldrich syndrome (WAS) is an immune deficiency with thrombopenia resulting from mutations in the WASP gene. This gene normally encodes the Wiskott-Aldrich syndrome protein (WASP), a major Cytoskeletal regulator expressed in hematopoietic cells. Gene therapy is a promising option for the treatment of WAS, requiring that clinically applicable WASP gene transfer vectors demonstrate efficacy in preclinical studies. Here, we describe a self-inactivating HIV-1-derived lentiviral vector encoding human WASP and show that it effectively transduced bone marrow progenitor cells of WASP knockout (WKO) mice. Transplantation of these transduced cells into lethally irradiated WKO recipients led to stable expression of WASP and correction of immune, inflammatory and Cytoskeletal Defects. Splenic T-cell proliferation was restored, podosomes were reinstated on bone-marrow-derived dendritic cells and colon inflammation was reduced. This shows for the first time (a) that Cytoskeletal Defects can be corrected in WKO mice, (b) that human WASP is biologically active in mice and (c) that a lentiviral vector is effective to express human WASP in vivo over several months. These data support further development of such lentiviral vectors for the gene therapy of WAS.
Jochen H Weishaupt - One of the best experts on this subject based on the ideXlab platform.
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profilin 1 with the amyotrophic lateral sclerosis associated mutation t109m displays unaltered actin binding and does not affect the actin cytoskeleton
BMC Neuroscience, 2015Co-Authors: Axel Freischmidt, Marcel Schopflin, Marisa S Feiler, Annkatrin Fleck, Albert C Ludolph, Jochen H WeishauptAbstract:Background The recent identification of several mutations in PFN1, a protein involved in actin dynamics, strengthens the hypothesis that pathology of amyotrophic lateral sclerosis is linked to Cytoskeletal Defects. Impaired actin binding is a common denominator of several PFN1 mutations associated with amyotrophic lateral sclerosis, although further mechanisms may also contribute to the death of motor neurons. In this study we examine the actin binding properties of PFN1 carrying the causal T109M mutation and its effects on the actin cytoskeleton.
