TY - JOUR
T1 - Microtubule destabilization and nuclear entry are sequential steps leading to toxicity in Huntington's disease
AU - Trushina, Eugenia
AU - Heldebrant, Michael P.
AU - Perez-Terzic, Carmen M.
AU - Bortolon, Ryan
AU - Kovtun, Irina V.
AU - Badger, John D.
AU - Terzic, Andre
AU - Estévez, Alvaro
AU - Windebank, Anthony J.
AU - Dyer, Roy B.
AU - Yao, Janet
AU - McMurray, Cynthia T.
PY - 2003/10/14
Y1 - 2003/10/14
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.2034961100
DO - 10.1073/pnas.2034961100
M3 - Article
C2 - 14527999
AN - SCOPUS:0142123112
SN - 0027-8424
VL - 100
SP - 12171
EP - 12176
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 21
ER -