| First Author | Kim YJ | Year | 2006 |
| Journal | Neurobiol Dis | Volume | 22 |
| Issue | 2 | Pages | 346-56 |
| PubMed ID | 16423528 | Mgi Jnum | J:111314 |
| Mgi Id | MGI:3653585 | Doi | 10.1016/j.nbd.2005.11.012 |
| Citation | Kim YJ, et al. (2006) Lysosomal proteases are involved in generation of N-terminal huntingtin fragments. Neurobiol Dis 22(2):346-56 |
| abstractText | N-terminal mutant huntingtin (N-mhtt) fragments form inclusions and cause cell death in vitro. Mutant htt expression stimulates autophagy and increases levels of lysosomal proteases. Here, we show that lysosomal proteases, cathepsins D, B and L, affected mhtt processing and levels of cleavage products (cp) known as A and B, which form inclusions. Adding inhibitors of cathepsin D, B and L to clonal striatal cells reduced mhtt, especially mhtt fragment cp A. Mutant htt fully degraded in cathepsin-L-treated lysates but formed stable N-mhtt fragments upon exposure to cathepsin D. Mutagenesis analysis of htt cDNA suggested that cathepsin D and the protease for cp A may cleave htt in the same region. Brain lysates from HD knock-in mice expressed N-mhtt fragments that accumulated with cathepsin D treatment and declined with aspartyl protease inhibition. Findings implicate lysosomal proteases in formation of N-mhtt fragments and clearance of mhtt. |
