Proteasome dysfunction underlies HERC2-linked neurodevelopmental disorder with Angelman-like clinical features - PubMed
6 hours ago
- #HERC2
- #Proteasome Dysfunction
- #Neurodevelopmental Disorder
- Biallelic hypomorphic variants in the E3 ubiquitin ligase HERC2 cause a neurodevelopmental disorder resembling Angelman syndrome, with features like global developmental delay, intellectual disability, autism spectrum features, and movement abnormalities.
- Quantitative proteomic analysis using biotinylated ubiquitin identified HERC2 targets, including subunits of major multimeric complexes such as the proteasome, tRNA-biosynthesis machinery, microtubule-associated assemblies, vesicle-coat complexes, centrosomes, and Ski and GATOR2 complexes.
- The proteasome was the most prominently affected complex, with up to eleven proteins required for assembly of the 19S regulatory particle showing HERC2-dependent ubiquitylation.
- HERC2 recognizes unassembled proteasome subunits via chaperone-mediated interactions and targets them for proteasomal degradation; loss of this mechanism in HERC2-deficient cells alters proteasomal activity.
- Patient-derived fibroblasts with the pathogenic variant c.1781 C > T (p.Pro594Leu) exhibit impaired processing of 19S subunits and aberrantly increased proteasome activity.
- The findings establish a link between HERC2-related neurodevelopmental disorder and impaired proteasome activity, elucidating molecular mechanisms and suggesting potential therapeutic strategies.