Trushina, Eugenia;
Heldebrant, Michael P.;
Perez-Terzic, Carmen M.;
Bortolon, Ryan;
Kovtun, Irina V.;
Badger, John D.;
Terzic, Andre;
Estévez, Alvaro;
Windebank, Anthony J.;
Dyer, Roy B.;
Yao, Janet;
McMurray, Cynthia T.
Microtubule Destabilization and Nuclear Entry Are Sequential Steps Leading to Toxicity in Huntington's Disease
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Medientyp:
E-Artikel
Titel:
Microtubule Destabilization and Nuclear Entry Are Sequential Steps Leading to Toxicity in Huntington's Disease
Beteiligte:
Trushina, Eugenia;
Heldebrant, Michael P.;
Perez-Terzic, Carmen M.;
Bortolon, Ryan;
Kovtun, Irina V.;
Badger, John D.;
Terzic, Andre;
Estévez, Alvaro;
Windebank, Anthony J.;
Dyer, Roy B.;
Yao, Janet;
McMurray, Cynthia T.
Erschienen:
National Academy of Sciences, 2003
Erschienen in:Proceedings of the National Academy of Sciences of the United States of America
Beschreibung:
<p>There has been a longstanding debate regarding the role of proteolysis in Huntington's disease. The toxic peptide theory posits that N-terminal cleavage fragments of mutant Huntington's disease protein [mutant huntingtin (mhtt)] enter the nucleus to cause transcriptional dysfunction. However, recent data suggest a second model in which proteolysis of full-length mhtt is inhibited. Importantly, the two competing theories differ with respect to subcellular distribution of mhtt at initiation of toxicity: nuclear if cleaved and cytoplasmic in the absence of cleavage. Using quantitative single-cell analysis and time-lapse imaging, we show here that transcriptional dysfunction is "downstream" of cytoplasmic dysfunction. Primary and reversible toxic events involve destabilization of microtubules mediated by full-length mhtt before cleavage. Restoration of microtubule structure by taxol inhibits nuclear entry and increases cell survival.</p>