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Molecular and Cellular Biology, September 2004, p. 8195-8209, Vol. 24, No. 18
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.18.8195-8209.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mutant Huntingtin Impairs Axonal Trafficking in Mammalian Neurons In Vivo and In Vitro

Eugenia Trushina,1,{dagger} Roy B. Dyer,1,{dagger} John D. Badger II,1 Daren Ure,2 Lars Eide,1,3 David D. Tran,4 Brent T. Vrieze,1 Valerie Legendre-Guillemin,5 Peter S. McPherson,5 Bhaskar S. Mandavilli,6 Bennett Van Houten,6 Scott Zeitlin,7 Mark McNiven,8 Ruedi Aebersold,9 Michael Hayden,10 Joseph E. Parisi,11 Erling Seeberg,3 Ioannis Dragatsis,12 Kelly Doyle,1 Anna Bender,1 Celin Chacko,1 and Cynthia T. McMurray1,4,8*

Department of Molecular Pharmacology and Experimental Therapeutics,1 Division of Neuroimmunology,2 Neuroscience Program, Mayo Medical School,4 Department of Biochemistry and Molecular Biology,8 Departments of Laboratory Medicine and Pathology and Neurology, Mayo ClinicFoundation, Rochester, Minnesota,11 Department of Neuroscience, University of Virginia, Charlottesville, Virginia,7 Institute for Systems Biology, Seattle, Washington,9 Department of Medical Genetics, University of British Columbia, Vancouver,10 Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canada,5 Centre of Molecular Biology and Neuroscience and Department of Molecular Biology, Institute of Medical Microbiology, University of Oslo, The National Hospital, Oslo, Norway,3 National Institute of Environmental Health Sciences, National Institutes of Health, Raleigh, North Carolina,6 Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee,12

Received 24 March 2004/ Returned for modification 25 May 2004/ Accepted 28 June 2004

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.

* Corresponding author. Mailing address: Department of Molecular Pharmacology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Phone: (507) 284-1597. Fax: (507) 284-9111. E-mail: mcmurray.cynthia{at}mayo.edu.

{dagger} E.T. and R.B.D. contributed equally.

Molecular and Cellular Biology, September 2004, p. 8195-8209, Vol. 24, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.18.8195-8209.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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