Microtubule destabilization and nuclear entry are sequential steps leading to toxicity in Huntington's disease

Eugenia Trushina, Michael P. Heldebrant, Carmen M. Perez-Terzic, Ryan Bortolon, Irina V. Kovtun, John D. Badger, Andre Terzic, Alvaro Estévez, Anthony J. Windebank, Roy B. Dyer, Janet Yao, Cynthia T. McMurray

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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.

Original languageEnglish (US)
Pages (from-to)12171-12176
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number21
StatePublished - Oct 14 2003


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