Perturbation with intrabodies reveals that calpain cleavage is required for degradation of huntingtin exon 1.

ABSTRACT:

Background

Proteolytic processing of mutant huntingtin (mHtt), the protein that causes Huntington's disease (HD), is critical for mHtt toxicity and disease progression. mHtt contains several caspase and calpain cleavage sites that generate N-terminal fragments that are more toxic than full-length mHtt. Further processing is then required for the degradation of these fragments, which in turn, reduces toxicity. This unknown, secondary degradative process represents a promising therapeutic target for HD.

Methodology/principal findings

We have used intrabodies, intracellularly expressed antibody fragments, to gain insight into the mechanism of mutant huntingtin exon 1 (mHDx-1) clearance. Happ1, an intrabody recognizing the proline-rich region of mHDx-1, reduces the level of solu

SUBMITTER: Southwell AL 

PROVIDER: S-EPMC3031625 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature