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Ultrasensitive quantitative measurement of huntingtin phosphorylation at residue S13

By Cariulo, Cristina; Verani, Margherita; Martufi, Paola; Ingenito, Raffaele; Finotto, Marco; Deguire, Sean M.; Lavery, Daniel J.; Toledo-Sherman, Leticia; Lee, Ramee; Doherty, Elizabeth M.; et al
From Biochemical and Biophysical Research Communications (2020), 521(3), 549-554. Language: English, Database: CAPLUS, DOI:10.1016/j.bbrc.2019.09.097

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by an expansion of a CAG triplet repeat (encoding for a polyglutamine tract) within the first exon of the huntingtin gene. Expression of the mutant huntingtin (mHTT) protein can result in the prodn. of N-terminal fragments with a robust propensity to form oligomers and aggregates, which may be causally assocd. with HD pathol. Several lines of evidence indicate that N17 phosphorylation or pseudophosphorylation at any of the residues T3, S13 or S16, alone or in combination, modulates mHTT aggregation, subcellular localization and toxicity. Consequently, increasing N17 phosphorylation has been proposed as a potential therapeutic approach. However, developing genetic/pharmacol. tools to quantify these phosphorylation events is necessary in order to subsequently develop tool modulators, which is difficult given the transient and incompletely penetrant nature of such post-translational modifications. Here we describe the first ultrasensitive sandwich immunoassay that quantifies HTT phosphorylated at residue S13 and demonstrate its utility for specific analyte detection in preclin. models of HD.

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