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Published online May 26, 2008
doi:10.1083/jcb.200710158
The Journal of Cell Biology, Vol. 181, No. 5, 803-816
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Wang et al.
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 Suppression of neuropil aggregates and neurological symptoms by an intracellular antibody implicates the cytoplasmic toxicity of mutant huntingtin

Chuan-En Wang1, Hui Zhou1, John R. McGuire1, Vincenzo Cerullo2, Brendan Lee2,3, Shi-Hua Li1, and Xiao-Jiang Li1

1 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
2 Department of Molecular and Human Genetics, 3 Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030

Correspondence to X.-J. Li: xiaoli{at}genetics.emory.edu

Mutant huntingtin accumulates in the neuronal nuclei and processes, which suggests that its subcellular localization is critical for the pathology of Huntington's disease (HD). However, the contribution of cytoplasmic mutant huntingtin and its aggregates in neuronal processes (neuropil aggregates) has not been rigorously explored. We generated an intracellular antibody (intrabody) whose binding to a unique epitope of human huntingtin is enhanced by polyglutamine expansion. This intrabody decreases the cytotoxicity of mutant huntingtin and its distribution in neuronal processes. When expressed in the striatum of HD mice via adenoviral infection, the intrabody reduces neuropil aggregate formation and ameliorates neurological symptoms. Interaction of the intrabody with mutant huntingtin increases the ubiquitination of cytoplasmic huntingtin and its degradation. These findings suggest that the intrabody reduces the specific neurotoxicity of cytoplasmic mutant huntingtin and its associated neurological symptoms by preventing the accumulation of mutant huntingtin in neuronal processes and promoting its clearance in the cytoplasm.

Abbreviations used in this paper: CMV, cytomegalovirus; HD, Huntington's disease; htt, huntingtin; polyP, polyproline; polyQ, polyglutamine; scFv, single-chain Fv.


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Huntington's disease protein extends its reach
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