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Phosphorylation of threonine 3: Implications for huntingtin aggregation and neurotoxicity

  • Author(s): Aiken, CT
  • Steffan, JS
  • Guerrero, CM
  • Khashwji, H
  • Lukacsovich, T
  • Simmons, D
  • Purcell, JM
  • Menhaji, K
  • Zhu, YZ
  • Green, K
  • LaFerla, F
  • Huang, L
  • Thompson, LM
  • Marsh, JL
  • et al.
Abstract

Huntingtin (Htt) is a widely expressed protein that causes tissue-specific degeneration when mutated to contain an expanded polyglutamine (poly(Q)) domain. Although Htt is large, 350 kDa, the appearance of amino-terminal fragments of Htt in extracts of postmortem brain tissue from patients with Huntington disease (HD), and the fact that an amino-terminal fragment, Htt exon 1 protein (Httex1p), is sufficient to cause disease in models of HD, points to the importance of the amino-terminal region of Htt in the disease process. The first exon of Htt encodes 17 amino acids followed by a poly(Q) repeat of variable length and culminating with a proline-rich domain of 50 amino acids. Because modifications to this fragment have the potential to directly affect pathogenesis in several ways, we have surveyed this fragment for potential post-translational modifications that might affect Htt behavior and detected several modifications of Httex1p. Here we report that the most prevalent modifications of Httex1p are NH2-terminal acetylation and phosphorylation of threonine 3 (pThr-3). We demonstrate that pThr-3 occurs on full-length Htt in vivo, and that this modification affects the aggregation and pathogenic properties of Htt. Thus, therapeutic strategies that modulate these events could in turn affect Htt pathogenesis. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

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