TY - JOUR
T1 - Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro
AU - Trushina, Eugenia
AU - Dyer, Roy B.
AU - Badger, John D.
AU - Ure, Daren
AU - Eide, Lars
AU - Tran, David D.
AU - Vrieze, Brent T.
AU - Legendre-Guillemin, Valerie
AU - McPherson, Peter S.
AU - Mandavilli, Bhaskar S.
AU - Van Houten, Bennett
AU - Zeitlin, Scott
AU - McNiven, Mark
AU - Aebersold, Ruedi
AU - Hayden, Michael
AU - Parisi, Joseph E.
AU - Seeberg, Erling
AU - Dragatsis, Ioannis
AU - Doyle, Kelly
AU - Bender, Anna
AU - Chacko, Celin
AU - McMurray, Cynthia T.
PY - 2004/9
Y1 - 2004/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=4444316194&partnerID=8YFLogxK
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U2 - 10.1128/MCB.24.18.8195-8209.2004
DO - 10.1128/MCB.24.18.8195-8209.2004
M3 - Article
C2 - 15340079
AN - SCOPUS:4444316194
SN - 0270-7306
VL - 24
SP - 8195
EP - 8209
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 18
ER -