Huntington’s disease protein modified semi-synthetically

In work that could lead to Huntington’s disease therapeutics and diagnostics, scientists have synthesized and studied modified forms of exon1, a key segment of mutant huntingtin, the protein that causes the condition. Huntington’s is a progressive neurodegenerative disorder that destroys brain neurons, leading to loss of movement control and impaired thinking. It is caused by the formation of mutant-huntingtin aggregates, which clog neurons. Posttranslational modifications (PTMs) that enzymes make on huntingtin, such as phosphorylation and acetylation, might be useful as targets of drugs and diagnostic probes. But determining the effects of huntingtin PTMs and huntingtin-modifying enzymes has been difficult. Hilal A. Lashuel of the Swiss Federal Institute of Technology, Lausanne (EPFL), and coworkers have now developed a method that addresses that problem. The technique creates all known PTMs of exon1 semisynthetically—by native chemical ligation and desulfurization of bacterially expressed PTM peptides (Angew. Chem. Int. Ed. 2017, DOI: 10.1002/anie.201611750). With the PTMs in hand, the researchers discovered a phosphorylation that inhibits huntingtin aggregation and an acetylation that may reverse the effect of that phosphorylation.