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Title: Mechanisms of G4C2 derived dipeptide repeat protein toxicity in Drosophila models of C9ALS/FTD
Author: Solomon, Daniel Adam
ISNI:       0000 0004 7656 5243
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2018
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A G4C2 hexanucleotide repeat expansion in the gene C9ORF72 is the most common cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). Although intronic, the G4C2 repeat is translated in the absence of an ATG start codon through a mechanism known as repeat-associated non-ATG translation resulting in the production of five different dipeptide-repeat proteins (DPRs). These DPRs form inclusions in brains of C9+ ALS and FTD sufferers. Further, C9+ patients are also characterised by cytoplasmic inclusions of the protein TDP-43, whose dysfunction is causally related to ALS and FTD. However, the pathogenic mechanisms underlying C9ALS/FTD and its relation to TDP-43 remain elusive. I have characterised numerous transgenic Drosophila to study G4C2 and DPR toxicity, and its relation to TDP-43 dysfunction. These Drosophila models of C9ALS/FTD are characterised by behavioural deficits that varied in age of onset and severity. The characteristics of motor impairment and subsequent neurodegeneration were dependent on the levels and identity of DPRs produced rather than G4C2 RNA. Severe, early onset phenotypes correlated with the presence of poly-GR whereas high levels of poly-GP and poly-GA correlated with late onset phenotypes. Non-G4C2 derived poly-GR caused a cytoplasmic accumulation of Drosophila TDP-43 (TBPH) whilst non-G4C2 derived poly-GA sequestered TBPH into inclusions. No change in TBPH localisation was seen following G4C2 RNA expression only. These alterations were accompanied with changes in the localisation of importins α2 and α3, the Drosophila homologues of karyopherins KPNA2 and KPNA4, respectively. However, expression and localisation of nucleocytoplasmic transport components such as RanGAP and nuclear pore complex proteins previously implicated in C9ALS/FTD appeared unperturbed. Further, cytoplasmic mislocalisation of TBPH enhanced DPR levels and cytotoxicity. Similar phenotypes were observed for patient frontal cortex in sporadic FTD and C9FTD; with KPNA4 being depleted from the nucleus and overlapping with TDP-43 inclusions. Taken together, these findings establish DPR accumulation as a cause of TDP-43 proteinopathy.
Supervisor: Hirth, Frank ; Gallo, Jean-Marc Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available