Site-specific ubiquitination of pathogenic huntingtin attenuates its deleterious effects

Significance The hallmark of neurodegenerative disorders (e.g., Alzheimer’s, Parkinson’s, and Huntington’s disease) is the generation of aggregated proteins in different brain regions. These large aggregates originate from smaller, invisible, and soluble oligomers/aggregates and are believed to be sequestered from essential cellular machineries and, therefore, to attenuate/postpone the pathologic process. That, in contrast to the smaller ones that are thought to inhibit basic cellular pathways by trapping their components. The role played in this process by ubiquitin—which normally targets proteins for degradation—is unknown. Here, we show that ubiquitination of pathogenic Htt is important for its efficient aggregation and probably sequestration. Abolishing its ubiquitination results in generation of numerous smaller and less visible aggregates that are particularly harmful to cells.