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Title: Investigation of dysregulation of TDP-43 and its role in molecular pathology
Author: Herzog, Jeremías Simón
ISNI:       0000 0004 5992 7265
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2016
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TAR-DNA-binding protein 43 kDa (TDP-43) is an RNA/DNA binding protein that is involved in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and a number of other neurological diseases that have been currently classified as TDP-43 proteinopathies. Defects in the control of TDP-43 expression levels may contribute to the neurodegeneration process observed in patients. TDP-43 autoregulation depends on a particular 700 nucleotides long sequence, the TOP Binding Region (TDPBR) within the TDP-43 3' UTR which contains several low affinity binding sites for TDP-43. If TDP-43 nuclear levels rise, increased binding to the TDPBR can trigger in a fraction of the nascent pre-mRNA molecules, a specific splicing event that removes the main poly(A) site, leading to an alternative poly(A) transcript that promotes mRNA instability. In the first part of this thesis I have determined that constitutive spliceosome formation across the intron 7 leads to low RNA and protein TDP-43 production. This event is in part caused by an altered nucleo-cytoplasmic distribution of the RNA. In the second part of the study, using a series of minigenes, I mapped some of the splicing cis regulatory elements within the TDPBR and the consequence of the variations of these elements in TDP-43 autoregulation. These data indicates that the elements within intron 7 act in an orchestrated way to sense the TDP-43 level variations. Furthermore, I demonstrated that the distance between the intron 7 and the pOly(A)2, can explain the reduced levels of TDP-43 observed when autoregulation is triggered. In conclusion this mechanism represents a novel type of auto-regulatory pathway to control cell viability, which acts through pre-mRNA alternative splicing and polyadenylation leading to mRNA degradation that is quite distinct from nonsense mediated decay (NMD).
Supervisor: Baralle, Francisco E. ; Fisher, Elizabeth Sponsor: International Centre for Genetic Engineering & Biotechnology
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available