A multifunctional, multi-pathway intracellular localization signal in Huntingtin

Nuclear accumulation of the polyglutamine-expanded mutant huntingtin protein remains one of the most predictive cell biological phenotypes of Huntington’s disease (HD) progression in patient brain samples and mouse models of the disease. Yet, the relationship between huntingtin nuclear import, neuronal dysfunction and toxicity is not fully understood and it remains unclear whether nuclear accumulation is required for disease onset. Here, we discuss several studies that have guided current understanding of this subject, and highlight our recent data detailing the discovery of a karyopherin β1/β2-type nuclear localization signal near the N-terminus of huntingtin. This signal can function through multiple pathways of nuclear import, and may also be responsible for huntingtin import into the primary cilium. This work represents a significant step forward in our knowledge of the regulatory pathways that govern huntingtin nuclear accumulation and will allow direct examination of both normal and mutant huntingtin nuclear function. This work also suggests a re-examination of the cell biology of any protein that contains a multi-pathway nuclear localization signal. The possibility of targeting huntingtin nuclear import therapeutically and the potential impacts of such a strategy for the treatment of HD are also discussed.