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The Journal of Neuroscience, September 3, 2008, 28(36):9013-9020; doi:10.1523/JNEUROSCI.2747-08.2008

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Neurobiology of Disease
Intrabodies Binding the Proline-Rich Domains of Mutant Huntingtin Increase Its Turnover and Reduce Neurotoxicity

Amber L. Southwell,¹ Ali Khoshnan,¹ Denise E. Dunn,^2,3 Charles W. Bugg,¹ Donald C. Lo,^2,3 and Paul H. Patterson¹

¹Division of Biology, California Institute of Technology, Pasadena, California 91125, ²Center for Drug Discovery, and ³Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27704

Correspondence should be addressed to Paul H. Patterson, Division of Biology, California Institute of Technology, 216-76, Pasadena, CA 91125. Email: php{at}caltech.edu

Although expanded polyglutamine (polyQ) repeats are inherently toxic, causing at least nine neurodegenerative diseases, the protein context determines which neurons are affected. The polyQ expansion that causes Huntington's disease (HD) is in the first exon (HDx-1) of huntingtin (Htt). However, other parts of the protein, including the 17 N-terminal amino acids and two proline (polyP) repeat domains, regulate the toxicity of mutant Htt. The role of the P-rich domain that is flanked by the polyP domains has not been explored. Using highly specific intracellular antibodies (intrabodies), we tested various epitopes for their roles in HDx-1 toxicity, aggregation, localization, and turnover. Three domains in the P-rich region (PRR) of HDx-1 are defined by intrabodies: MW7 binds the two polyP domains, and Happ1 and Happ3, two new intrabodies, bind the unique, P-rich epitope located between the two polyP epitopes. We find that the PRR-binding intrabodies, as well as V_L12.3, which binds the N-terminal 17 aa, decrease the toxicity and aggregation of HDx-1, but they do so by different mechanisms. The PRR-binding intrabodies have no effect on Htt localization, but they cause a significant increase in the turnover rate of mutant Htt, which V_L12.3 does not change. In contrast, expression of V_L12.3 increases nuclear Htt. We propose that the PRR of mutant Htt regulates its stability, and that compromising this pathogenic epitope by intrabody binding represents a novel therapeutic strategy for treating HD. We also note that intrabody binding represents a powerful tool for determining the function of protein epitopes in living cells.

Key words: Huntington; neurodegeneration; gene therapy; immunotherapy; intrabody; polyproline

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Received June 16, 2008; accepted July 24, 2008.

Correspondence should be addressed to Paul H. Patterson, Division of Biology, California Institute of Technology, 216-76, Pasadena, CA 91125. Email: php{at}caltech.edu

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				A. L. Southwell, J. Ko, and P. H. Patterson Intrabody Gene Therapy Ameliorates Motor, Cognitive, and Neuropathological Symptoms in Multiple Mouse Models of Huntington's Disease J. Neurosci., October 28, 2009; 29(43): 13589 - 13602. [Abstract] [Full Text] [PDF]

				J. Legleiter, G. P. Lotz, J. Miller, J. Ko, C. Ng, G. L. Williams, S. Finkbeiner, P. H. Patterson, and P. J. Muchowski Monoclonal Antibodies Recognize Distinct Conformational Epitopes Formed by Polyglutamine in a Mutant Huntingtin Fragment J. Biol. Chem., August 7, 2009; 284(32): 21647 - 21658. [Abstract] [Full Text] [PDF]

eLetters:

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Is the proline-rich domain of mutant huntingtin involved in the regulation of its stability?

Alessio Cardinale, et al.

J. Neurosci. Online, 19 Sep 2008 [Full text]

Re: Is the proline-rich domain of mutant huntingtin involved in the regulation of its stability?

Amber L Southwell, et al.

J. Neurosci. Online, 22 Apr 2009 [Full text]

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