{"343891":{"#nid":"343891","#data":{"type":"event","title":"Meredith Jackrel, University of Pennsylvania","body":[{"value":"\u003Cp\u003EPotentiated Hsp104 variants antagonize diverse proteotoxic misfolding events\u003C\/p\u003E","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003E\u003Cstrong\u003EPotentiated Hsp104 variants antagonize diverse proteotoxic misfolding events\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003EThere are no therapies that reverse the proteotoxic misfolding events that underpin fatal neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Parkinson\u2019s disease (PD). Hsp104, a\u0026nbsp;conserved hexameric AAA+ protein from yeast, solubilizes disordered aggregates and amyloid but has no metazoan homolog and only limited activity against human neurodegenerative disease proteins. Here, I will describe our work to reprogram Hsp104 to rescue TDP-43, FUS, and \u03b1-synuclein proteotoxicity by mutating single residues in helix 1, 2, or 3 of the middle domain or the small domain of nucleotide-binding domain 1.\u0026nbsp;Potentiated Hsp104 variants enhance aggregate dissolution, restore proper protein localization, suppress proteotoxicity, and in a \u003Cem\u003EC.\u0026nbsp;elegans\u003C\/em\u003E PD model attenuate dopaminergic neurodegeneration. Furthermore, these potentiated variants suppress the toxicity and aggregation induced by missense mutant versions of these proteins that are associated with more severe neurodegenerative disease phenotypes. Potentiating mutations reconfigure how Hsp104 subunits collaborate, desensitize Hsp104 to inhibition, obviate any requirement for Hsp70, and enhance ATPase, translocation, and unfoldase activity. Our work establishes that disease-associated aggregates and amyloid are tractable targets and that enhanced disaggregases can restore proteostasis and mitigate neurodegeneration.\u003C\/p\u003E","format":"limited_html"}],"field_summary_sentence":[{"value":"Meredith Jackrel, University of Pennsylvania"}],"uid":"27964","created_gmt":"2014-11-10 15:13:13","changed_gmt":"2017-04-13 21:21:12","author":"Jasmine Martin","boilerplate_text":"","field_publication":"","field_article_url":"","field_event_time":{"event_time_start":"2014-11-18T10:00:00-05:00","event_time_end":"2014-11-18T10:00:00-05:00","event_time_end_last":"2014-11-18T10:00:00-05:00","gmt_time_start":"2014-11-18 15:00:00","gmt_time_end":"2014-11-18 15:00:00","gmt_time_end_last":"2014-11-18 15:00:00","rrule":null,"timezone":"America\/New_York"},"extras":[],"groups":[{"id":"1275","name":"School of Biological Sciences"}],"categories":[],"keywords":[{"id":"109181","name":"Meredith Jackrel"}],"core_research_areas":[],"news_room_topics":[],"event_categories":[{"id":"1795","name":"Seminar\/Lecture\/Colloquium"}],"invited_audience":[{"id":"78751","name":"Undergraduate students"},{"id":"78761","name":"Faculty\/Staff"},{"id":"174045","name":"Graduate students"}],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cp\u003EIf you have questions about logistics or would like to set up an appointment with the speaker, please contact the School of Biology\u0027s administrative office at \u003Ca href=\u0022mailto:bio-admin@biology.gatech.edu\u0022\u003Ebio-admin@biology.gatech.edu\u003C\/a\u003E.\u003C\/p\u003E","format":"limited_html"}],"email":[],"slides":[],"orientation":[],"userdata":""}}}