Microtubule destabilization and nuclear entry are sequential steps leading to toxicity in Huntington's disease.
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.
Trushina
Eugenia
E
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, Second Street SW, Rochester, MN 55905, USA.
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
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
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017239:Paclitaxel