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Mol Cell Biol. 2004 Sep;24(18):8195-209.

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

Author information

1
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicFoundation, Rochester, Minnesota 55905, USA.

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.

PMID:
15340079
PMCID:
PMC515048
DOI:
10.1128/MCB.24.18.8195-8209.2004
[Indexed for MEDLINE]
Free PMC Article

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