| First Author | Gafni J | Year | 2012 |
| Journal | J Neurosci | Volume | 32 |
| Issue | 22 | Pages | 7454-65 |
| PubMed ID | 22649225 | Mgi Jnum | J:184973 |
| Mgi Id | MGI:5427022 | Doi | 10.1523/JNEUROSCI.6379-11.2012 |
| Citation | Gafni J, et al. (2012) 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. J Neurosci 32(22):7454-7465 |
| abstractText | 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. |
