title: 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.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, Second Street SW, Rochester, MN 55905, USA.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Trushina
authors.forename: Michael P
authors.initials: MP
authors.lastname: Heldebrant
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Perez-Terzic
authors.forename: Ryan
authors.initials: R
authors.lastname: Bortolon
authors.forename: Irina V
authors.initials: IV
authors.lastname: Kovtun
authors.forename: John D
authors.initials: JD
authors.lastname: Badger
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
authors.forename: Alvaro
authors.initials: A
authors.lastname: Estévez
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Windebank
authors.forename: Roy B
authors.initials: RB
authors.lastname: Dyer
authors.forename: Janet
authors.initials: J
authors.lastname: Yao
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: McMurray
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D017239:Paclitaxel / Q000494:pharmacology
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017239:Paclitaxel