Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro

Eugenia Trushina, Roy B. Dyer, John D. Badger, Daren Ure, Lars Eide, David D. Tran, Brent T. Vrieze, Valerie Legendre-Guillemin, Peter S. McPherson, Bhaskar S. Mandavilli, Bennett Van Houten, Scott Zeitlin, Mark McNiven, Ruedi Aebersold, Michael Hayden, Joseph E. Parisi, Erling Seeberg, Ioannis Dragatsis, Kelly Doyle, Anna BenderCelin Chacko, Cynthia T. McMurray

Research output: Contribution to journalArticle

372 Scopus citations

Abstract

Recent data in invertebrates demonstrated that huntingtin (htt) is essential for fast axonal trafficking. Here, we provide direct and functional evidence that htt is involved in fast axonal trafficking in mammals. Moreover, expression of full-length mutant htt (mhtt) impairs vesicular and mitochondrial trafficking in mammalian neurons in vitro and in whole animals in vivo. Particularly, mitochondria become progressively immobilized and stop more frequently in neurons from transgenic animals. These defects occurred early in development prior to the onset of measurable neurological or mitochondrial abnormalities. Consistent with a progressive loss of function, wild-type htt, trafficking motors, and mitochondrial components were selectively sequestered by mhtt in human Huntington's disease-affected brain. Data provide a model for how loss of htt function causes toxicity; mhtt-mediated aggregation sequesters htt and components of trafficking machinery leading to loss of mitochondrial motility and eventual mitochondrial dysfunction.

Original languageEnglish (US)
Pages (from-to)8195-8209
Number of pages15
JournalMolecular and cellular biology
Volume24
Issue number18
DOIs
StatePublished - Sep 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Trushina, E., Dyer, R. B., Badger, J. D., Ure, D., Eide, L., Tran, D. D., Vrieze, B. T., Legendre-Guillemin, V., McPherson, P. S., Mandavilli, B. S., Van Houten, B., Zeitlin, S., McNiven, M., Aebersold, R., Hayden, M., Parisi, J. E., Seeberg, E., Dragatsis, I., Doyle, K., ... McMurray, C. T. (2004). Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Molecular and cellular biology, 24(18), 8195-8209. https://doi.org/10.1128/MCB.24.18.8195-8209.2004