HNRNP Q suppresses polyglutamine huntingtin aggregation by post‐transcriptional regulation of vaccinia‐related kinase 2

Abstract Misfolded proteins with abnormal polyglutamine (polyQ) expansion cause neurodegenerative disorders, including Huntington's disease. Recently, it was found that polyQ aggregates accumulate as a result of vaccinia‐related kinase 2 ( VRK 2)‐mediated degradation of TCP ‐1 ring complex ( TR iC)/chaperonin‐containing TCP ‐1 ( CCT ), which has an essential role in the prevention of polyQ protein aggregation and cytotoxicity. The levels of VRK 2 are known to be much higher in actively proliferating cells but are maintained at a low level in the brain via an unknown mechanism. Here, we found that basal levels of neuronal cell‐specific VRK 2 mRNA are maintained by post‐transcriptional, rather than transcriptional, regulation. Moreover, heterogeneous nuclear ribonucleoprotein Q ( HNRNP Q) specifically binds to the 3ʹuntranslated region of VRK 2 mRNA in neuronal cells to reduce the mRNA stability. As a result, we found a dramatic decrease in CCT 4 protein levels in response to a reduction in HNRNP Q levels, which was followed by an increase in polyQ aggregation in human neuroblastoma cells and mouse cortical neurons. Taken together, these results provide new insights into how neuronal HNRNP Q decreases VRK 2 mRNA stability and contributes to the prevention of Huntington's disease, while also identifying new prognostic markers of HD. image