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HNRNP Q suppresses polyglutamine huntingtin aggregation by post‐transcriptional regulation of vaccinia‐related kinase 2
Author(s) -
Ryu Hye Guk,
Kim Sangjune,
Lee Saebom,
Lee Eunju,
Kim HyoJin,
Kim DoYeon,
Kim KyongTai
Publication year - 2019
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14638
Subject(s) - huntingtin , heterogeneous nuclear ribonucleoprotein , biology , messenger rna , three prime untranslated region , microbiology and biotechnology , untranslated region , ribonucleoprotein , protein kinase a , huntington's disease , vaccinia , kinase , rna , genetics , gene , mutant , disease , medicine , recombinant dna
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.

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