Mutant huntingtin affects p53 function in a context‐dependent manner in a cell model of Huntington's disease

Abstract

Huntington's disease (HD) is an adult‐onset neurodegenerative disease caused by expansion of a polyglutamine (polyQ) repeat in the N‐terminal region of the huntingtin (htt) protein. In HD, multiple N‐terminal mutant htt fragments, smaller than the first 500 amino acids, have been found to accumulate in disease tissue. These N‐terminal htt fragments associate abnormally with many cellular proteins, disturbing their function. The p53 tumor suppressor protein has been shown to abnormally interact with mutant htt and is associated with cellular dysfunction in HD. However, it is unknown whether different htt fragments affect p53 function differentially. Here, we investigated the affect of different length N‐terminal mutant htt fragments on p53 localization and function in a human cell model of HD. We found that shorter htt fragments cause more accumulation of p53 protein in the nucleus which is associated with decreased cell viability. Our results demonstrate the importance of mutant htt protein context in HD. While the p53 pathway is implicated as a potential target to ameliorate Huntington disease progression, the therapeutic benefit may be limited by the relative abundance of shorter N‐terminal htt fragments in target cells.Support or Funding InformationThis work was supported by the National Science Foundation under Grant No. 1458212. JC was supported in part by a faculty fellowship from the Appalachian College Association.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.