Huntingtin turnover: modulation of huntingtin degradation by cAMP-dependent protein kinase A (PKA) phosphorylation of C-HEAT domain Ser2550
Huntington’s disease (HD) is a neurodegenerative disorder caused by an inherited unstable HTT CAG repeat that expands further, thereby eliciting a disease process that may be initiated by polyglutamine-expanded huntingtin or a short polyglutamine-product. Phosphorylation of selected candidate residues is reported to mediate polyglutamine-fragment degradation and toxicity. In this manuscript, CGM Investigators Ihn Sik Seong, Marcy MacDonald and colleagues used deep mass spectrometry-based phosphoproteomics to systematically identify sites in purified huntingtin and in the endogenous protein. The analyses identified as many as 95 total phospho-sites in Huntingtin, including phosphorylation of C-HEAT Ser2550 by AMP-dependent protein kinase (PKA), which was found to hasten huntingtin degradation. This work highlights categories of phosphosites and biological processes that regulate huntingtin degradation that are relevant to HD pathogenesis and merit further study.