Twist of messenger Fate: novel mechanisms for TDP43 in modulating mRNA decay and alternative polyadenylation

Potrich, Valentina (2017) Twist of messenger Fate: novel mechanisms for TDP43 in modulating mRNA decay and alternative polyadenylation. PhD thesis, University of Trento.

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TDP43 is an ubiquitously expressed RNA-binding protein implicated in several aspects of RNA metabolism. It can shuttle between the nucleus and the cytoplasm; however, when it is mutated in some familial Amyotrophic Lateral Sclerosis (ALS) cases, it undergoes nuclear clearance and cytoplasmic accumulation, driving neuronal degeneration. The same phenotype is present in patients bearing ALS-inducing mutations in other genes and ALS sporadic patients, defining TDP43 proteinopathy as a common feature in this pathology. Why does it cause specific motor neuron death? Our quantitative proteomics analysis of the TDP43 interactome revealed the interaction with components of the mRNA surveillance pathway, suggesting a still undiscovered function in nonsense-mediated decay. We demonstrated that TDP43 acts translation- and SMG1-dependently as a mRNA decay enhancer of specific transcripts by binding their 3’UTR. In particular, it leads to the down-regulation of transcripts with a long 3’UTR. From our sequencing data of spinal cords from TDP43Q331K transgenic mouse model and of motor neuron-like NSC-34 cells silenced for TDP43 emerged that TDP43 plays another striking role in the 3’UTR, modulating mRNA alternative polyadenylation and promoting the generation of shorter transcripts. This finding is supported by the direct interaction of TDP43 with the cleavage stimulation factor, a core component of the polyadenylation machinery. These results broaden our knowledge of the role of TDP43 in the post-transcriptional gene expression regulation. The impairment of these two biological processes by TDP43 proteinopathy could have implications in ALS pathogenesis, representing possible new targets for therapeutic approaches.

Item Type:Doctoral Thesis (PhD)
Doctoral School:Biomolecular Sciences
PhD Cycle:29
Subjects:Area 05 - Scienze biologiche > BIO/11 BIOLOGIA MOLECOLARE
Area 05 - Scienze biologiche > BIO/13 BIOLOGIA APPLICATA
Funders:PAT- Provincia Autonoma di Trento
Repository Staff approval on:10 Oct 2017 09:32

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