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Modulation of neuronal function by tau, alpha synuclein or carbon dioxide
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Hill, Emily (2021) Modulation of neuronal function by tau, alpha synuclein or carbon dioxide. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3679330
Abstract
The misfolding and aggregation of protein is a characteristic hallmark of neurodegenerative disorders, most notably of amyloid beta and tau in Alzheimer’s disease and alpha synuclein in Parkinson’s disease. There is gathering evidence that early soluble aggregates of these proteins are the most toxic species. In this thesis I have used whole-cell patch clamp recording to quantitively analyse the cellular and sub-cellular effects of introducing tau or alpha synuclein aggregates on neuronal or synaptic function in single neurons.
I have demonstrated that full-length tau oligomers (oTau) induce marked changes to action potential dynamics, synaptic transmission and plasticity that were not observed with monomeric tau. Consistent with these electrophysiological changes, oTau could diffuse from the injection site (soma) to synaptic sites within 30 minutes of recording. This study had provided valuable new insight into the actions of tau oligomers within single neurons. I then looked to define the mechanisms underlying these changes using tau truncations. CFRAG (aa124-444) oTau caused a shift in the spike-initiation threshold, mediating the increase in excitability. While NFRAG (aa1-123) tau aggregates and monomers both resulted in comparable changes to AP waveform as full length-oTau. Recording isolated voltage-gated sodium channels highlighted a tau-mediated reduction in both the half-activation and maximal sodium channel conductance.
Using the same method, I have demonstrated that introduction of aggregated αSyn into dopaminergic neurons in the substantia nigra significantly increased conductance and decreased excitability, an effect which could be partially prevented by pre-incubation of the slices with Glibenclamide. While evaluating these neurons, I discovered that they have an unexpected connexin hemichannel-mediated CO2-sensitivity phenotype. These cells are located in regions of the brain that are involved in movement, reward, and arousal behaviour. Physiological changes in PCO2 markedly altered whole-cell conductance and excitability. This work suggests a mechanism by which CO2, could alter complex goal-directed behaviours.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QP Physiology R Medicine > RC Internal medicine |
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Library of Congress Subject Headings (LCSH): | Protein folding, Nervous system -- Degeneration, Amyloid beta-protein, Alpha-synuclein, tau Proteins | ||||
Official Date: | March 2021 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | School of Life Sciences | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Wall, Mark ; Richardson, Magnus J. E. | ||||
Sponsors: | Biotechnology and Biological Sciences Research Council (Great Britain) ; Midlands Integrative Biosciences Training Partnership ; Alzheimer's Research UK | ||||
Format of File: | |||||
Extent: | 313 leaves : illustrations | ||||
Language: | eng |
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