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Caspase-6 activity in a BACHD mouse modulates steady-state levels of mutant huntingtin protein but is not necessary for production of a 586 amino acid proteolytic fragment.

Huntington's disease (HD) is caused by a mutation in the huntingtin (htt) gene encoding an expansion of glutamine repeats at the N terminus of the Htt protein. Proteolysis of Htt has been identified as a critical pathological event in HD models. In particular, it has been postulated that proteolysis of Htt at the putative caspase-6 cleavage site (at amino acid Asp-586) plays a critical role in disease progression and pathogenesis. However, whether caspase-6 is indeed the essential enzyme that cleaves Htt at this site in vivo has not been determined. To evaluate, we crossed the BACHD mouse model with a caspase-6 knock-out mouse (Casp6(-/-)). Western blot and immunocytochemistry confirmed the lack of caspase-6 protein in Casp6(-/-) mice, regardless of HD genotype. We predicted the Casp6(-/-) mouse would have reduced levels of caspase-6 Htt fragments and increased levels of full-length Htt protein. In contrast, we found a significant reduction of full-length mutant Htt (mHtt) and fragments in the striatum of BACHD Casp6(-/-) mice. Importantly, we detected the presence of Htt fragments consistent with cleavage at amino acid Asp-586 of Htt in the BACHD Casp6(-/-) mouse, indicating that caspase-6 activity cannot fully account for the generation of the Htt 586 fragment in vivo. Our data are not consistent with the hypothesis that caspase-6 activity is critical in generating a potentially toxic 586 aa Htt fragment in vivo. However, our studies do suggest a role for caspase-6 activity in clearance pathways for mHtt protein.

Pubmed ID: 22649225


  • Gafni J
  • Papanikolaou T
  • Degiacomo F
  • Holcomb J
  • Chen S
  • Menalled L
  • Kudwa A
  • Fitzpatrick J
  • Miller S
  • Ramboz S
  • Tuunanen PI
  • Lehtimäki KK
  • Yang XW
  • Park L
  • Kwak S
  • Howland D
  • Park H
  • Ellerby LM


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

May 30, 2012

Associated Grants

  • Agency: NINDS NIH HHS, Id: NS40251
  • Agency: NINDS NIH HHS, Id: R01 NS040251
  • Agency: NINDS NIH HHS, Id: R01 NS049501
  • Agency: NINDS NIH HHS, Id: R01 NS074312

Mesh Terms

  • Age Factors
  • Amino Acids
  • Animals
  • Aspartic Acid
  • Body Weight
  • Brain
  • Caspase 6
  • Cells, Cultured
  • Corpus Striatum
  • Disease Models, Animal
  • Embryo, Mammalian
  • Exploratory Behavior
  • Female
  • Gene Expression Regulation
  • Huntington Disease
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Motor Activity
  • Nerve Tissue Proteins
  • Neurons
  • Proteolysis
  • RNA, Small Interfering
  • Rotarod Performance Test
  • Trinucleotide Repeat Expansion
  • Ubiquitination