Huntington's disease protein contributes to RNA-mediated gene silencing through association with Argonaute and P bodies/neuronal granules.

摘要

Huntington's disease is a dominant autosomal neurodegenerative disorder caused by an expansion of polyglutamines in the Huntingtin (Htt) protein, whose cellular function remains controversial. To gain insight into Htt function, we purified epitope-tagged Htt and identified Argonaute as associated proteins. Co-localization studies demonstrated Htt and Ago2 to be present in P bodies, and depletion of Htt showed compromised RNA-mediated gene silencing. Two sets of HD mouse model cells expressing mutant Htt showed fewer P bodies and reduced reporter gene silencing activity compared with wild-type counterparts. We went on to show that Htt is present in a subset of dendritic RNA granules and interacts/colocalizes with several known dendritic mRNAs. Further we have shown Htt traffics in live neurons and can co-traffic with staufen. We believe Htt functions in several pathways linked to post-transcriptional gene silencing and may bridge the miRNA pathway with cytoplasmic polyadenylation through interaction with argonaute and symplekin. These data suggest that the previously reported transcriptional deregulation in HD may be attributed in part to mutant Htt's role in post-transcriptional processes.