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


ABSTRACT: 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.

SUBMITTER: Trushina E 

PROVIDER: S-EPMC218731 | biostudies-literature | 2003 Oct

REPOSITORIES: biostudies-literature

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

Trushina Eugenia E   Heldebrant Michael P MP   Perez-Terzic Carmen M CM   Bortolon Ryan R   Kovtun Irina V IV   Badger John D JD   Terzic Andre A   Estévez Alvaro A   Windebank Anthony J AJ   Dyer Roy B RB   Yao Janet J   McMurray Cynthia T CT  

Proceedings of the National Academy of Sciences of the United States of America 20031003 21


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 tox  ...[more]

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