Phosphorylation of huntingtin at residue T3 is decreased in Huntington’s disease and modulates mutant huntingtin protein conformation.

By Cariulo, Cristina; Azzollini, Lucia; Verani, Margherita; Martufi, Paola; Boggio, Roberto; Chiki, Anass; Deguire, Sean M.; Cherubini, Marta; Gines, Silvia; Marsh, J. Lawrence; et al
From Proceedings of the National Academy of Sciences of the United States of America (2017), 114(50), E10809-E10818. Language: English, Database: CAPLUS, DOI:10.1073/pnas.1705372114

Posttranslational modifications can have profound effects on the biol. and biophys. properties of proteins assocd. with misfolding and aggregation. However, their detection and quantification in clin. samples and an understanding of the mechanisms underlying the pathol. properties of misfolding- and aggregation-prone proteins remain a challenge for diagnostics and therapeutics development. We have applied an ultrasensitive immunoassay platform to develop and validate a quant. assay for detecting a posttranslational modification (phosphorylation at residue T3) of a protein assocd. with polyglutamine repeat expansion, namely Huntingtin, and characterized its presence in a variety of preclin. and clin. samples. We find that T3 phosphorylation is greatly reduced in samples from Huntington’s disease models and in Huntington’s disease patients, and we provide evidence that bona-fide T3 phosphorylation alters Huntingtin exon 1 protein conformation and aggregation properties. These findings have significant implications for both mechanisms of disease pathogenesis and the development of therapeutics and diagnostics for Huntington’s disease.