Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro.
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.
Trushina
Eugenia
E
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicFoundation, Rochester, Minnesota 55905, USA.
Dyer
Roy B
RB
Badger
John D
JD
Ure
Daren
D
Eide
Lars
L
Tran
David D
DD
Vrieze
Brent T
BT
Legendre-Guillemin
Valerie
V
McPherson
Peter S
PS
Mandavilli
Bhaskar S
BS
Van Houten
Bennett
B
Zeitlin
Scott
S
McNiven
Mark
M
Aebersold
Ruedi
R
Hayden
Michael
M
Parisi
Joseph E
JE
Seeberg
Erling
E
Dragatsis
Ioannis
I
Doyle
Kelly
K
Bender
Anna
A
Chacko
Celin
C
McMurray
Cynthia T
CT
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
C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D004247:DNA