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The role of TIGAR in Parkinson´s Disease

Robles López, Karla Lourdes (2017) The role of TIGAR in Parkinson´s Disease. PhD thesis, University of Sheffield.

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Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease. The pathological hallmark of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Common identifiable genetic causes of early onset PD (EOPD) are Parkin and PINK1 mutations. Tigarb, the orthologue of human TIGAR (TP53–Induced Glycolysis and Apoptosis Regulator), up-regulation was demonstrated in a zebrafish pink1-/- model along with dopaminergic cell loss and mitochondrial dysfunction (Flinn et al., 2013). Tigarb knockdown rescued the dopaminergic neurons and mitochondrial dysfunction. Here, tigarb upregulation suggests an involvement in PD neuropathology. Therefore, we investigated whether TIGAR is present in the human brain and elucidate its relationship between TIGAR protein and the Lewy body pathology. TIGAR was found in the Lewy Bodies and Neurites in SNpc of sporadic PD and Dementia with Lewy bodies patients. TIGAR protein was not found in the ubiquitylated inclusions of motor neurone disease or multiple system atrophy, suggesting a degree of disease specificity. TIGAR role was investigated in fibroblasts from PD patients and controls. TIGAR is expressed and translated in human fibroblasts. TIGAR gene expression and protein level between controls and parkin-mutant fibroblasts was not significantly different. TIGAR cellular localisation was not affected in parkin mutant fibroblasts after rotenone toxic and cellular stress exposure. TIGAR involvement in autophagy was not found in sporadic PD patients. RNAi methods for efficient TIGAR and PINK1 knockdown were designed in using HEK 293T cells as host line, where TIGAR and PINK1 deficiency showed no significant effect in the ATP production and mitochondrial morphology. CRISPR/Cas9 and microRNAs mediated knockdown were investigated to assess gene function and to select the best approach with reproducible and reliable results.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield)
The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Identification Number/EthosID: uk.bl.ethos.729497
Depositing User: Dr. Karla Lourdes Robles López
Date Deposited: 11 Dec 2017 09:14
Last Modified: 15 Jun 2020 13:46
URI: http://etheses.whiterose.ac.uk/id/eprint/18939

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