Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1386
pubmed:dateCreated
1999-8-26
pubmed:abstractText
A unifying feature of the CAG expansion diseases is the formation of intracellular aggregates composed of the mutant polyglutamine-expanded protein. Despite the presence of aggregates in affected patients, the precise relationship between aggregates and disease pathogenesis is unresolved. Results from in vivo and in vitro studies of mutant huntingtin have led to the hypothesis that nuclear localization of aggregates is critical for the pathology of Huntington's disease (HD). We tested this hypothesis using a 293T cell culture model system by comparing the frequency and toxicity of cytoplasmic and nuclear huntingtin aggregates. Insertion of nuclear import or export sequences into huntingtin fragments containing 548 or 151 amino acids was used to reverse the normal localization of these proteins. Changing the subcellular localization of the fragments did not influence their total aggregate frequency. There were also no significant differences in toxicity associated with the presence of nuclear compared with cytoplasmic aggregates. These studies, together with findings in transgenic mice, suggest two phases for the pathogenesis of HD, with the initial toxicity in the cytoplasm followed by proteolytic processing of huntingtin, nuclear translocation with increased nuclear concentration of N-terminal fragments, seeding of aggregates and resultant apoptotic death. These findings support the nucleus and cytosol as subcellular sites for pathogenesis in HD.
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-10085113, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-3802100, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-4150800, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-6215820, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-7477378, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-7477379, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-8599106, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-8612237, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-8696339, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-8968739, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9140394, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9267033, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9292723, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9302293, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9328463, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9353120, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9353121, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9359692, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9382472, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9384612, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9413985, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9427237, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9462738, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9462744, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9499423, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9535906, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9536080, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9536081, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9536097, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9580663, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9606203, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9620770, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9635424, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9650759, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9665608, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9666478, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9700187, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9721092, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9736019, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9778246, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9778247, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9886069, http://linkedlifedata.com/resource/pubmed/commentcorrection/10434304-9887328
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0962-8436
pubmed:author
pubmed:issnType
Print
pubmed:day
29
pubmed:volume
354
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1047-55
pubmed:dateRevised
2009-11-18
pubmed:meshHeading
pubmed:year
1999
pubmed:articleTitle
Evidence for both the nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington's disease in cell culture and in transgenic mice expressing mutant huntingtin.
pubmed:affiliation
Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada.
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