Major hnRNP proteins act as general TDP-43 functional modifiers both in Drosophila and human neuronal cells. Issue 13 (31st May 2017)

• Record Type: Journal Article
• Authors: Appocher, Chiara; Mohagheghi, Fatemeh; Cappelli, Sara; Stuani, Cristiana; Romano, Maurizio; Feiguin, Fabian; Buratti, Emanuele
• Is Part Of: Nucleic acids research. Volume 45:Issue 13(2017)
• Page Start: 8026
• Page End: 8045
• Publication Date: 2017-05-31
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkx477
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: 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.