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Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity

Khoshnan, Ali and Ko, Jan and Patterson, Paul H. (2002) Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity. Proceedings of the National Academy of Sciences of the United States of America, 99 (2). pp. 1002-1007. ISSN 0027-8424. PMCID PMC117420.

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We have generated eight mAbs (MW1-8) that bind the epitopes polyglutamine (polyQ), polyproline (polyP), or the C terminus of exon 1 in huntingtin (htt) protein. In the brains of Huntington's disease (HD) mouse models, the anti-polyQ mABs bind to various cytoplasmic compartments, whereas the anti-polyP and anti-C terminus mAbs bind nuclear inclusions containing htt. To use these mAbs as intracellular perturbation agents, we have cloned and expressed the antigen-binding domains of three of the mAbs as single-chain variable region fragment Abs (scFvs). In 293 cells cotransfected with htt exon 1 containing an expanded polyQ domain, MW1, MW2, and MW7 scFvs colocalize with htt exon 1. Moreover, these scFvs coimmunoprecipitate with htt exon 1 in cell extracts. In perturbation experiments, MW7 scFv, recognizing the polyP domains of htt, significantly inhibits aggregation as well as the cell death induced by mutant htt protein. In contrast, MW1 and MW2 scFvs, recognizing the polyQ stretch, stimulate htt aggregation and apoptosis. Therefore, these anti-htt scFvs can be used to investigate the role of the polyP and polyQ domains in HD pathogenesis, and antibody binding to the polyP domain has potential therapeutic value in HD.

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Additional Information:Copyright © 2002 by the National Academy of Sciences. Communicated by Giuseppe Attardi, California Institute of Technology, Pasadena, CA, November 28, 2001 (received for review August 30, 2001). Published online before print January 15, 2002, 10.1073/pnas.022631799 We thank Vivian Hook, George Jackson, and George Lawless for generously providing antibodies and DNA constructs, and Doreen McDowell for administrative assistance. David Anderson provided camera and microscope access. Ethan Signer was an important source of information and facilitated obtaining reagents. The technical assistance of Sarah Teegarden and Melinda Owens is greatly appreciated. This work is supported by the Cure Huntington’s Disease Initiative of the Hereditary Disease Foundation. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
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Hereditary Disease FoundationUNSPECIFIED
Issue or Number:2
PubMed Central ID:PMC117420
Record Number:CaltechAUTHORS:KHOpnas02
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1116
Deposited By: Tony Diaz
Deposited On:20 Dec 2005
Last Modified:02 Oct 2019 22:40

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