Xu Haifei, An Juan Ji, Xu Baoji
Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, Florida, United States of America.
PLoS One. 2017 May 11;12(5):e0177610. doi: 10.1371/journal.pone.0177610. eCollection 2017.
Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion within exon1 of the HTT gene. The gene generates two mRNA variants that carry either a short or long 3' untranslated region (3'UTR) while encoding the same protein. It remains unknown whether the two mRNA variants play distinct roles in HD pathogenesis. We found that the long HTT 3'UTR was capable of guiding mRNA to neuronal dendrites, suggesting that some long-form HTT mRNA is transported to dendrites for local protein synthesis. To assay roles of two HTT mRNA variants in cell bodies, we expressed mRNA harboring HTT exon1 containing 23x or 145x CAGs with the short or long 3'UTR. We found that mutant mRNA containing the short 3'UTR produced more protein aggregates and caused more apoptosis in both cultured neurons and HEK293 cells, compared with mutant mRNA containing the long 3'UTR. Although the two 3'UTRs did not affect mRNA stability, we detected higher levels of protein synthesis from mRNA containing the short 3'UTR than from mRNA containing the long 3'UTR. These results indicate that the long HTT 3'UTR suppresses translation. Thus, short-form mutant HTT mRNA will be more efficient in producing toxic protein than its long-form counterpart.
亨廷顿舞蹈症（HD）是一种神经退行性疾病，由HTT基因外显子1内的CAG重复序列扩增引起。该基因产生两种mRNA变体，它们携带短或长的3'非翻译区（3'UTR），同时编码相同的蛋白质。这两种mRNA变体在HD发病机制中是否发挥不同作用尚不清楚。我们发现，长的HTT 3'UTR能够将mRNA引导至神经元树突，这表明一些长形式的HTT mRNA被转运至树突进行局部蛋白质合成。为了分析两种HTT mRNA变体在细胞体中的作用，我们表达了含有23个或145个CAG的HTT外显子1且带有短或长3'UTR的mRNA。我们发现，与含有长3'UTR的突变mRNA相比，含有短3'UTR的突变mRNA在培养的神经元和HEK293细胞中产生了更多的蛋白质聚集体，并导致了更多的细胞凋亡。虽然这两种3'UTR不影响mRNA稳定性，但我们检测到含有短3'UTR的mRNA的蛋白质合成水平高于含有长3'UTR的mRNA。这些结果表明，长的HTT 3'UTR抑制翻译。因此，短形式的突变HTT mRNA在产生有毒蛋白质方面将比其长形式的对应物更有效。
