{"134091":{"#nid":"134091","#data":{"type":"news","title":"Cell Contents May be Key to Controlling Toxicity of Huntington\u2019s Disease Protein","body":[{"value":"\u003Cp\u003ENew research into the cell-damaging effects of Huntington\u2019s disease suggests a new approach for identifying possible therapeutic targets for treating the nerve-destroying disorder.\u003C\/p\u003E\u003Cp\u003EHuntington\u2019s disease causes the progressive breakdown of nerve cells in the brain and affects an individual\u2019s movement, cognition and mental state. Genetically, the disease is associated with a mutation in the Huntingtin gene that causes the huntingtin protein to be produced with an extended region containing the amino acid glutamine.\u003C\/p\u003E\u003Cp\u003EThe mechanisms that control the severity and onset of the disease are poorly understood, as individuals with the same amount of expansion in their huntingtin proteins experience differences in toxicity and onset of the disease. \u0026nbsp;\u003C\/p\u003E\u003Cp\u003EA new study led by Georgia Institute of Technology researchers suggests that the toxic effects of the huntingtin protein on cells may not be driven exclusively by the length of the protein\u2019s expansion, but also by which other proteins are present in the cell.\u003C\/p\u003E\u003Cp\u003EThe researchers placed human huntingtin protein with an expanded region, called a polyglutamine tract, into yeast cells and found toxicity differences that were based on the other protein aggregates -- called prions -- present in the cells.\u003C\/p\u003E\u003Cp\u003E\u201cThis study clarifies genetic and epigenetic mechanisms that modulate polyglutamine\u2019s toxicity on cells and establishes a new approach for identifying potential therapeutic targets through characterization of pre-existing proteins in the cell,\u201d said \u003Ca href=\u0022http:\/\/www.biology.gatech.edu\/people\/yury-chernoff\/?id=yury-chernoff\u0022\u003EYury Chernoff\u003C\/a\u003E, a professor in the \u003Ca href=\u0022http:\/\/www.biology.gatech.edu\/\u0022\u003ESchool of Biology\u003C\/a\u003E at Georgia Tech. \u201cWhile this study was conducted in yeast, it is possible that there are differences in aggregated proteins present in human cells as well, which are causing variation in huntingtin toxicity among individuals.\u201d\u003C\/p\u003E\u003Cp\u003EThe results of the study were published in the April 2012 issue of the journal \u003Cem\u003E\u003Ca href=\u0022http:\/\/dx.doi.org\/10.1371\/journal.pgen.1002634\u0022\u003EPLoS Genetics\u003C\/a\u003E\u003C\/em\u003E. This work was supported by the National Institutes of Health and the Hereditary Disease Foundation.\u003C\/p\u003E\u003Cp\u003EAlso contributing to this research were former Georgia Tech graduate student He Gong and postdoctoral fellow Nina Romanova, University of North Carolina at Chapel Hill School of Medicine research assistant professor Piotr Mieczkowski, and Boston University School of Medicine professor Michael Sherman.\u003C\/p\u003E\u003Cp\u003EExpanded huntingtin forms clumps in human cells that are typically transported and stored in an internal compartment called an aggresome until they can be removed from the body. While the compartment is thought to protect the contents of the cell from the toxic contents inside the aggresome, the current study shows that huntingtin molecules inside an aggresome can still be toxic to the cell.\u003C\/p\u003E\u003Cp\u003EIn the study, aggresome formation in the cells containing the prion form of the Rnq1 protein reduced the toxicity of the huntingtin protein in \u003Cem\u003ESaccharomyces cerevisiae \u003C\/em\u003Eyeast cells, whereas the huntingtin protein\u2019s toxicity remained in the presence of the prion form of translation release factor Sup35.\u003C\/p\u003E\u003Cp\u003E\u201cIt remains uncertain whether the toxicity was primarily driven by sequestration of Sup35 into the aggresome or by its sequestration into the smaller huntingtin protein aggregates that remained in the cytoplasm,\u201d explained Chernoff, who is also director of the Center for Nanobiology of the Macromolecular Assembly Disorders (\u003Ca href=\u0022http:\/\/www.nanomad.gatech.edu\/\u0022\u003ENanoMAD\u003C\/a\u003E). \u201cWhile Sup35 was detected in the aggresome, we don\u2019t know if the functional fraction of Sup35 was sequestered there.\u201d\u003C\/p\u003E\u003Cp\u003EIn a follow-on experiment, the researchers increased the level of another release factor, Sup45, in the presence of Sup35 and found that this combination counteracted the toxicity.\u003C\/p\u003E\u003Cp\u003E\u201cWhile the Rnq1 and Sup35 prions did not cause significant toxicity on their own, the results show that prion composition in the cell drove toxicity,\u201d noted Chernoff. \u201cPrions modulated which proteins were sequestered by the aggresome, as proteins associated with the pre-existing prions were more likely to be sequestered, such as Sup45 because of its association with Sup35.\u201d\u003C\/p\u003E\u003Cp\u003EIt remains unknown if polyglutamines can sequester the human versions of the Sup35 and Sup45 release factors, but this study shows the possibility that organisms may differ by the protein composition in their cells, and this in turn may influence their susceptibility to polyglutamine disorders such as Huntington\u2019s disease.\u003C\/p\u003E\u003Cp\u003E\u003Cem\u003EResearch reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under award numbers GM058763, GM093294 and GM086890. The content is solely the responsibility of the principal investigators and does not necessarily represent the official views of the NIH.\u003C\/em\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EResearch News \u0026amp; Publications Office\u003Cbr \/\u003E Georgia Institute of Technology\u003Cbr \/\u003E 75 Fifth Street, N.W., Suite 314\u003Cbr \/\u003E Atlanta, Georgia 30308 USA\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EMedia Relations Contacts:\u003C\/strong\u003E Abby Robinson (abby@innovate.gatech.edu; 404-385-3364) or John Toon (jtoon@gatech.edu; 404-894-6986)\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EWriter: \u003C\/strong\u003EAbby Robinson\u003C\/p\u003E","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003EA new study proposes novel therapeutic targets for treating Huntington\u2019s disease. The study found the toxic effects of the huntingtin protein on cells may not be driven exclusively by the length of the protein\u2019s expansion, but also by which other proteins are present in the cell.\u0026nbsp;\u003C\/p\u003E","format":"limited_html"}],"field_summary_sentence":[{"value":"A new study proposes novel therapeutic targets for treating Huntington\u2019s disease."}],"uid":"27206","created_gmt":"2012-06-06 08:39:06","changed_gmt":"2016-10-08 03:12:22","author":"Abby Vogel Robinson","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2012-06-06T00:00:00-04:00","iso_date":"2012-06-06T00:00:00-04:00","tz":"America\/New_York"},"extras":[],"hg_media":{"134081":{"id":"134081","type":"image","title":"Sup35 sequestration","body":null,"created":"1449178671","gmt_created":"2015-12-03 21:37:51","changed":"1475894763","gmt_changed":"2016-10-08 02:46:03","alt":"Sup35 sequestration","file":{"fid":"194758","name":"chernoff-sup35-polyglutamines-aggresome.jpg","image_path":"\/sites\/default\/files\/images\/chernoff-sup35-polyglutamines-aggresome_0.jpg","image_full_path":"http:\/\/hg.gatech.edu\/\/sites\/default\/files\/images\/chernoff-sup35-polyglutamines-aggresome_0.jpg","mime":"image\/jpeg","size":188945,"path_740":"http:\/\/hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/chernoff-sup35-polyglutamines-aggresome_0.jpg?itok=fXug37Po"}}},"media_ids":["134081"],"groups":[{"id":"1188","name":"Research Horizons"}],"categories":[{"id":"146","name":"Life Sciences and Biology"},{"id":"135","name":"Research"}],"keywords":[{"id":"35331","name":"Aggresome"},{"id":"4896","name":"College of Sciences"},{"id":"35311","name":"Huntingtin"},{"id":"35301","name":"huntingtin protein"},{"id":"35291","name":"Huntington\u0027s Disease"},{"id":"35321","name":"Polyglutamine"},{"id":"13831","name":"prion"},{"id":"35341","name":"Rnq1 protein"},{"id":"169501","name":"sup35"},{"id":"169502","name":"sup45"},{"id":"35381","name":"Toxicity"},{"id":"35371","name":"translation release factor"},{"id":"13827","name":"Yury Chernoff"}],"core_research_areas":[],"news_room_topics":[],"event_categories":[],"invited_audience":[],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cp\u003EAbby Robinson\u003Cbr \/\u003E Research News and Publications\u003Cbr \/\u003E \u003Ca href=\u0022mailto:abby@innovate.gatech.edu\u0022\u003Eabby@innovate.gatech.edu\u003C\/a\u003E\u003Cbr \/\u003E 404-385-3364\u003C\/p\u003E","format":"limited_html"}],"email":[],"slides":[],"orientation":[],"userdata":""}}}