Browsing All Posts By Huntington Chile
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28 Septiembre 2018 Estudio Legato-Hd: un estudio de fase 2 que evalúa la eficacia y seguridad de Laquinimod como tratamiento para la Enfermedad de Huntington.Active-Biotech-Poster-Presented-at-the-EHDN-2018-A-on-Legato-HD-Study-A-Phase-2-Study-Assessing-the-Efficacy-and-Safety-of-Laquinimod-as-a-Treatment-for-Huntington
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03 Agosto 2018 – HD Buz Nro. 262 Noticias en la Investigación de la Enfermedad de Huntington, en lenguaje sencillo, escrito por científico para la comunidad global de la Enfermedad de HuntingtonHD-Buzz-262
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01 Agosto 2018 – HD Buz Nro. 261 Noticias en la Investigación de la Enfermedad de Huntington, en lenguaje sencillo, escrito por científico para la comunidad global de la Enfermedad de Huntingtonhd-buzz-261
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12 Julio 2018 Una nueva visión de la enfermedad de Huntington puede abrir la puerta al desarrollo de fármacos
New insight into Huntington’s disease may open door to drug development
July 9, 2018, McMaster University
Professor Ray Truant (left) and Ph.D. student Laura Bowie of McMaster University have developed a new hypothesis on Huntington’s disease, published in PNAS, which shows promise to open new avenues for drug development for the condition. Credit: McMaster University
McMaster University researchers have developed a new theory on Huntington’s disease which is being welcomed for showing promise to open new avenues of drug development for the condition.
Huntington’s disease is caused by a mutation in the gene that makes the protein called huntingtin. A team of researchers led by McMaster has found there is a unique type of signalling coming from damaged DNA, that signals huntingtin activity in DNA repair, and that this signalling is defective in Huntington’s disease.A study developing the new hypothesis was published today in the Proceedings of the National Academy of Sciences (PNAS).
«The concept was that if we applied the signalling molecule back in excess, even orally, this signalling can be restored in the Huntington’s disease mouse brain,» said Laura Bowie, a Ph.D. student in the Department of Biochemistry and Biomedical Sciences at McMaster. «The net result was that we fixed the modification of huntingtin not seen in mutant huntingtin in Huntington’s disease.»
Using this hypothesis, the study team discovered a molecule called N6-furfuryladenine, derived from the repair of DNA damage, which corrected the defect seen in mutant huntingtin.
«Based on dosing by different ways of this molecule in mouse Huntington’s disease models, Huntington’s disease symptoms were reversed,» said Bowie. «The mutant huntingtin protein levels were also restored to normal, which was a surprise to us.»
Ray Truant, senior author on the study, has dedicated his career to Huntington’s disease research and how mutation leads to Huntington’s disease. His lab was the first to show that normal huntingtin was involved in DNA repair.
Truant argues that the traditional and controversial amyloid/protein misfolding hypothesis, where a group of proteins stick together forming brain deposits, is likely the result of the disease, rather than its cause. He said he considers this paper the most significant of his career.
«This is an important new lead and a new hypothesis, but it is important for people to know this is not a drug or cure,» said Truant, professor in the Department of Biochemistry and Biomedical Sciences at McMaster.
«This is the first new hypothesis for Huntington’s disease in 25 years that does not rely on the version of the amyloid hypothesis which has consistently failed in drug development for other diseases.»
Huntington’s disease is a hereditary, neurodegenerative illness with devastating physical, cognitive and emotional symptoms. Worldwide, approximately one of every 7,000 people can develop Huntington’s disease. Currently there is no treatment available to alter the course of the disease.
The study is an original and important contribution to the field of neurodegeneration, says Yves Joanette, scientific director of the Canadian Institutes of Health Research Institute of Aging. «This research shows how complex and diverse the routes to neurodegenerative processes in the brain can be,» said Joanette. «This study will inspire not only research on Huntington’s disease, but also in some of the contributing processes to the development of many other neurodegenerative diseases.»
Bev Heim-Myers, CEO of the Huntington Society of Canada, said: «The Huntington Society of Canada is proud to support such leading edge research. Innovative research initiatives, such as the work led by the team in Dr. Truant’s lab, including Ph.D. student Laurie Bowie, has the potential to transform HD research. The answers we find for Huntington’s disease will likely lead to better understanding of treatments for other neurological diseases and it is important that we continue this cross-talk amongst neurodegenerative diseases.»
Journal reference: Proceedings of the National Academy of Sciences
More Information: see below
Subscribers to PNAS can view the full study on the below URL
N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation http://www.pnas.org/content/early/2018/07/05/1801772115
PNAS July 9, 2018. 201801772; published ahead of print July 9, 2018. https://doi.org/10.1073/pnas.1801772115
Edited by Nancy E. Kleckner, Harvard University, Cambridge, MA, and approved June 19, 2018 (received for review January 31, 2018)
Authors: Laura E. Bowie, Tamara Maiuri, Melanie Alpaugh, Michelle Gabriel, Nicolas Arbez, Danny Galleguillos, Claudia L. K. Hung, Shreya Patel, Jianrun Xia, Nicholas T. Hertz, Christopher A. Ross, David W. Litchfield, Simonetta Sipione, and Ray Truant
Significance: We have discovered a molecule derived from DNA-damage repair that can correct the lack of phosphorylation of mutant huntingtin, the cause of Huntington’s disease (HD). In a mouse model, treatment reverses HD-like disease, and we see the lowering of mutant huntingtin levels to normal. The mechanism of this molecule is that it is processed to make a signal for kinase activity essential for repairing DNA. This mechanism is critical when neurons are stressed and have very low or absent energy levels. We propose that this molecule is a type of signaling from DNA-damage repair that occurs at dangerously low ATP levels.
Abstract: The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington’s disease (HD). We conducted high-content analysis to find compounds that could restore N17 phosphorylation. One lead compound from this screen was N6-furfuryladenine (N6FFA). N6FFA was protective in HD model neurons, and N6FFA treatment of an HD mouse model corrects HD phenotypes and eliminates cortical mutant huntingtin inclusions. We show that N6FFA restores N17 phosphorylation levels by being salvaged to a triphosphate form by adenine phosphoribosyltransferase (APRT) and used as a phosphate donor by casein kinase 2 (CK2). N6FFA is a naturally occurring product of oxidative DNA damage. Phosphorylated huntingtin functionally redistributes and colocalizes with CK2, APRT, and N6FFA DNA adducts at sites of induced DNA damage. We present a model in which this natural product compound is salvaged to provide a triphosphate substrate to signal huntingtin phosphorylation via CK2 during low-ATP stress under conditions of DNA damage, with protective effects in HD model systems.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1801772115/-/DCSupplemental.READ MORE +
11 Julio 2018 HD Buz Nro. 260 Noticias en la Investigación de la Enfermedad de Huntington, en lenguaje sencillo, escrito por científico para la comunidad global de la Enfermedad de HuntingtonHdBuzz-260
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09 Mayo 2018 HD Buz Nro. 258 Noticias en la Investigación de la Enfermedad de Huntington, en lenguaje sencillo, escrito por científico para la comunidad global de la Enfermedad de HuntingtonHDBuzz-258-HDSAs-Q-and-As-on-the-latest-huntingtin-lowering-update-from-Ionis-and-Roche-dtd.-4-26-2018
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10 Mayo 2018 HD Buz Nro. 259 Noticias en la Investigación de la Enfermedad de Huntington, en lenguaje sencillo, escrito por científico para la comunidad global de la Enfermedad de HuntingtonHDBuzz-259-New-collaboration-seeks-to-speed-Huntingtons-disease-drug-licensing-5-9-2018
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19 Abril 2018 HD Buz Nro. 257 Noticias en la Investigación de la Enfermedad de Huntington, en lenguaje sencillo, escrito por científico para la comunidad global de la Enfermedad de HuntingtonHDBuzz-257-en
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05 Abril 2018 HD Buz Nro. 256 Noticias en la Investigación de la Enfermedad de Huntington, en lenguaje sencillo, escrito por científico para la comunidad global de la Enfermedad de HuntingtonHDBuzz-256-en
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