title: Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro.
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.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicFoundation, Rochester, Minnesota 55905, USA.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Trushina
authors.forename: Roy B
authors.initials: RB
authors.lastname: Dyer
authors.forename: John D
authors.initials: JD
authors.lastname: Badger
authors.forename: Daren
authors.initials: D
authors.lastname: Ure
authors.forename: Lars
authors.initials: L
authors.lastname: Eide
authors.forename: David D
authors.initials: DD
authors.lastname: Tran
authors.forename: Brent T
authors.initials: BT
authors.lastname: Vrieze
authors.forename: Valerie
authors.initials: V
authors.lastname: Legendre-Guillemin
authors.forename: Peter S
authors.initials: PS
authors.lastname: McPherson
authors.forename: Bhaskar S
authors.initials: BS
authors.lastname: Mandavilli
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
authors.forename: Scott
authors.initials: S
authors.lastname: Zeitlin
authors.forename: Mark
authors.initials: M
authors.lastname: McNiven
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
authors.forename: Michael
authors.initials: M
authors.lastname: Hayden
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.forename: Erling
authors.initials: E
authors.lastname: Seeberg
authors.forename: Ioannis
authors.initials: I
authors.lastname: Dragatsis
authors.forename: Kelly
authors.initials: K
authors.lastname: Doyle
authors.forename: Anna
authors.initials: A
authors.lastname: Bender
authors.forename: Celin
authors.initials: C
authors.lastname: Chacko
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: McMurray
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001370:Axonal Transport / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D004247:DNA / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D008959:Models, Neurological; D009068:Movement; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D004247:DNA