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Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice.

The N-terminal 17 amino acids of huntingtin (NT17) can be phosphorylated on serines 13 and 16; however, the significance of these modifications in Huntington's disease pathogenesis remains unknown. In this study, we developed BAC transgenic mice expressing full-length mutant huntingtin (fl-mhtt) with serines 13 and 16 mutated to either aspartate (phosphomimetic or SD) or alanine (phosphoresistant or SA). Both mutant proteins preserve the essential function of huntingtin in rescuing knockout mouse phenotypes. However, fl-mhtt-induced disease pathogenesis, including motor and psychiatric-like behavioral deficits, mhtt aggregation, and selective neurodegeneration are abolished in SD but preserved in SA mice. Moreover, modification of these serines in expanded repeat huntingtin peptides modulates aggregation and amyloid fibril formation in vitro. Together, our findings demonstrate that serines 13 and 16 are critical determinants of fl-mhtt-induced disease pathogenesis in vivo, supporting the targeting of huntingtin NT17 domain and its modifications in HD therapy.

Pubmed ID: 20064390

Authors

  • Gu X
  • Greiner ER
  • Mishra R
  • Kodali R
  • Osmand A
  • Finkbeiner S
  • Steffan JS
  • Thompson LM
  • Wetzel R
  • Yang XW

Journal

Neuron

Publication Data

December 24, 2009

Associated Grants

  • Agency: NIA NIH HHS, Id: 2P01AG022074
  • Agency: NINDS NIH HHS, Id: 2R01NS39074
  • Agency: NINDS NIH HHS, Id: 2R01NS45491
  • Agency: NINDS NIH HHS, Id: 3R01NS049501-05S1
  • Agency: NINDS NIH HHS, Id: NS045283
  • Agency: NINDS NIH HHS, Id: NS52789
  • Agency: NINDS NIH HHS, Id: R01 NS049501
  • Agency: NINDS NIH HHS, Id: R01 NS049501-01
  • Agency: NINDS NIH HHS, Id: R01 NS049501-02
  • Agency: NINDS NIH HHS, Id: R01 NS049501-03
  • Agency: NINDS NIH HHS, Id: R01 NS049501-04
  • Agency: NINDS NIH HHS, Id: R01 NS049501-05
  • Agency: NINDS NIH HHS, Id: R01 NS049501-05S1
  • Agency: NIA NIH HHS, Id: R01AG019322
  • Agency: NINDS NIH HHS, Id: R01NS049501

Mesh Terms

  • Alanine
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Amyloid
  • Animals
  • Aspartic Acid
  • Disease Models, Animal
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Humans
  • Huntington Disease
  • Mice
  • Mice, Transgenic
  • Molecular Weight
  • Mutation
  • Nerve Degeneration
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Phenotype
  • Protein Structure, Tertiary
  • Serine
  • Trinucleotide Repeat Expansion