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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2011-3-8
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pubmed:abstractText |
Huntington's disease is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (encoded by HTT). PolyQ length determines disease onset and severity, with a longer expansion causing earlier onset. The mechanisms of mutant huntingtin-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in Huntington's disease pathogenesis. Here we tested whether mutant huntingtin impairs the mitochondrial fission-fusion balance and thereby causes neuronal injury. We show that mutant huntingtin triggers mitochondrial fragmentation in rat neurons and fibroblasts of individuals with Huntington's disease in vitro and in a mouse model of Huntington's disease in vivo before the presence of neurological deficits and huntingtin aggregates. Mutant huntingtin abnormally interacts with the mitochondrial fission GTPase dynamin-related protein-1 (DRP1) in mice and humans with Huntington's disease, which, in turn, stimulates its enzymatic activity. Mutant huntingtin-mediated mitochondrial fragmentation, defects in anterograde and retrograde mitochondrial transport and neuronal cell death are all rescued by reducing DRP1 GTPase activity with the dominant-negative DRP1 K38A mutant. Thus, DRP1 might represent a new therapeutic target to combat neurodegeneration in Huntington's disease.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-11302518,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-11514614,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-11703942,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-15340079,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-15716954,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-15878861,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-16272155,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-17051205,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-17053808,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-17500595,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-18337408,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-18568013,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-18617037,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-18951640,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-19039036,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-19228972,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-19342591,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-19726651,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-19752021,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-20463395,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-21383715,
http://linkedlifedata.com/resource/pubmed/commentcorrection/21336284-8968738
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
1546-170X
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pubmed:author |
pubmed-author:Bossy-WetzelEllaE,
pubmed-author:BossyBlaiseB,
pubmed-author:DeebZ EZE,
pubmed-author:EllismanMarkM,
pubmed-author:HaydenMichael RMR,
pubmed-author:KlinglmayrEvaE,
pubmed-author:LiotGeraldineG,
pubmed-author:MasliahEliezerE,
pubmed-author:PerkinsGuyG,
pubmed-author:PetrilliAlejandraA,
pubmed-author:PoquizPatrickP,
pubmed-author:PouladiMahmoud AMA,
pubmed-author:RouillerIsabelleI,
pubmed-author:SchwarzenbacherRobertR,
pubmed-author:SongWenjunW,
pubmed-author:TjongJonathanJ,
pubmed-author:ZhouYueY
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pubmed:issnType |
Electronic
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pubmed:volume |
17
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
377-82
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pubmed:dateRevised |
2011-9-13
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pubmed:meshHeading |
pubmed-meshheading:21336284-Animals,
pubmed-meshheading:21336284-Disease Models, Animal,
pubmed-meshheading:21336284-GTP Phosphohydrolases,
pubmed-meshheading:21336284-Humans,
pubmed-meshheading:21336284-Mice,
pubmed-meshheading:21336284-Microtubule-Associated Proteins,
pubmed-meshheading:21336284-Mitochondria,
pubmed-meshheading:21336284-Mitochondrial Proteins,
pubmed-meshheading:21336284-Mutation,
pubmed-meshheading:21336284-Nerve Tissue Proteins,
pubmed-meshheading:21336284-Nuclear Proteins,
pubmed-meshheading:21336284-Protein Binding
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pubmed:year |
2011
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pubmed:articleTitle |
Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity.
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pubmed:affiliation |
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA.
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