Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.748685
Title: Macroautophagy, alpha-synuclein and dopamine neurotransmission : implications for Parkinson's disease
Author: Hunn, Benjamin Henry Mcleod
ISNI:       0000 0004 7234 1955
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Abstract:
Parkinson's disease (PD) is an incurable neurological disease characterised by impairment of motor function, death of substantia nigra pars compacta (SNc) dopamine (DA) neurons and accumulation of the protein α-synuclein. Macroautophagy, a major process by which deleterious cellular contents are degraded, is implicated in both sporadic and genetic PD, and macroautophagy inducers are currently in PD clinical trials. However, little is known about the interaction between α-synuclein and macroautophagy in vivo. In this thesis, the interaction between impaired macroautophagy in DA neurons and α-synuclein was studied by generating novel transgenic mice. Mice were bred featuring conditional knockout of ATG7, a gene essential for macroautophagy, in DA neurons (ATG7cKODAT-IRES-cre), and expressing the full-length human α-synuclein gene (hSNCA). Mice carrying the ATG7cKODAT-IRES-cre genotype developed key features of PD, including loss of SNc DA neurons, reductions in caudate-putamen DA and the development of protein aggregates in DA neurons. Presence of the hSNCA gene had minimal effect on histological phenotypes. Paradoxically, ATG7cKODAT-IRES-cre mice displayed improvements in some elements of motor function, including increased locomotion, increased gait swing speed and improved motor coordination in old age. There was no effect of the hSNCA gene on behavioural phenotypes. In order to determine a physiological basis for the discrepancy between the neuropathological and motor phenotypes associated with the ATG7cKODAT-IRES-cre genotype, DA neurotransmission was examined using fast-scan cyclic voltammetry (FCV). FCV demonstrated that the ATG7cKODAT-IRES-cre genotype increased evoked DA levels, reduced the rate of DA reuptake, and increased evoked DA in response to repeated stimuli. The finding that impaired macroautophagy in DA neurons enhances DA neurotransmission was confirmed in a second transgenic mouse model. These data demonstrating that impaired macroautophagy enhances dopamine neurotransmission, thus improving behavioural phenotypes while worsening some pathological phenotypes, has direct implications for PD pathogenesis, drug discovery and clinical trials.
Supervisor: Cragg, Stephanie ; Wade-Martins, Richard Sponsor: Rhodes Trust ; Guarantors of Brain ; Parkinson's UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.748685  DOI: Not available
Keywords: Nervous system--Surgery ; Parkinson's disease ; Neurology ; Autophagy
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