Unknown

Dataset Information

0

N-alpha-acetylation of Huntingtin protein increases its propensity to aggregate.


ABSTRACT: Huntington's disease (HD) is a neurodegenerative disorder caused by a poly-CAG expansion in the first exon of the HTT gene, resulting in an extended poly-glutamine tract in the N-terminal domain of the Huntingtin (Htt) protein product. Proteolytic fragments of the poly-glutamine-containing N-terminal domain form intranuclear aggregates that are correlated with HD. Post-translational modification of Htt has been shown to alter its function and aggregation properties. However, the effect of N-terminal Htt acetylation has not yet been considered. Here, we developed a bacterial system to produce unmodified or N-terminally acetylated and aggregation-inducible Htt protein. We used this system together with biochemical, biophysical, and imaging studies to confirm that the Htt N-terminus is an in vitro substrate for the NatA N-terminal acetyltransferase and show that N-terminal acetylation promotes aggregation. These studies represent the first link between N-terminal acetylation and the promotion of a neurodegenerative disease and implicates NatA-mediated Htt acetylation as a new potential therapeutic target in HD.

SUBMITTER: Gottlieb L 

PROVIDER: S-EPMC8640455 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC3138907 | biostudies-literature
| S-EPMC3234273 | biostudies-literature
| S-EPMC2940108 | biostudies-literature
| S-EPMC8429736 | biostudies-literature
| S-EPMC5420564 | biostudies-literature
| S-EPMC6754563 | biostudies-literature
| S-EPMC3779647 | biostudies-literature
| S-EPMC3508451 | biostudies-literature
| S-EPMC4712450 | biostudies-literature
| S-EPMC2647740 | biostudies-literature