Major hnRNP proteins act as general TDP-43 functional modifiers both in Drosophila and human neuronal cells
Major hnRNP proteins act as general TDP-43 functional modifiers both in Drosophila and human neuronal cells
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DOI：
10.1093/nar/gkx477
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发表时间：
2017-07-27
影响因子：
14.9
通讯作者：
Buratti, Emanuele
中科院分区：
文献类型：
--
作者：
Appocher, Chiara;Mohagheghi, Fatemeh;Buratti, Emanuele
已知核因子TDP-43在几种神经退行性病变中起重要作用。通常，TDP-43是真核细胞核内丰富的蛋白质，其结合许多编码和非编码RNA并影响其加工。使用果蝇，我们已经进行了功能筛选，以建立主要的hnRNP蛋白影响TDP-43过表达/耗尽表型的能力。有趣的是，我们观察到降低hnRNP和TDP-43表达对果蝇运动能力具有普遍有害的影响。同时，我们的研究还确定了一组独特的hnRNP，能够在蝇眼中有效地挽救TDP-43毒性（Hrb 27 c，CG 42458，Glo和Syp）。最重要的是，在人神经元细胞系中去除Hrb 27 c（DAZAP 1）的人直系同源物可以纠正由TDP-43耗尽改变的几个前mRNA剪接事件。此外，使用RNA测序分析，我们表明，DAZAP 1和TDP-43可以共同调节大量的生物过程和分子功能的神经元/运动神经元病理生理学的潜在重要性。我们的研究结果表明，hnRNP表达水平的变化可以显着调节TDP-43的功能，并影响病理结果。
Nuclear factor TDP-43 is known to play an important role in several neurodegenerative pathologies. In general, TDP-43 is an abundant protein within the eukaryotic nucleus that binds to many coding and non-coding RNAs and influence their processing. Using Drosophila, we have performed a functional screening to establish the ability of major hnRNP proteins to affect TDP-43 overexpression/depletion phenotypes. Interestingly, we observed that lowering hnRNP and TDP-43 expression has a generally harmful effect on flies locomotor abilities. In parallel, our study has also identified a distinct set of hnRNPs that is capable of powerfully rescuing TDP-43 toxicity in the fly eye (Hrb27c, CG42458, Glo and Syp). Most importantly, removing the human orthologs of Hrb27c (DAZAP1) in human neuronal cell lines can correct several pre-mRNA splicing events altered by TDP-43 depletion. Moreover, using RNA sequencing analysis we show that DAZAP1 and TDP-43 can co-regulate an extensive number of biological processes and molecular functions potentially important for the neuron/motor neuron pathophysiology. Our results suggest that changes in hnRNP expression levels can significantly modulate TDP-43 functions and affect pathological outcomes.