The functional and pathological pathways of α-Synuclein
type: CreativeWork
description: The aberrant aggregation of intrinsically disordered α-Synuclein (αS) is associated with Parkinson’s disease (PD) and other neurodegenerative diseases termed synucleopathies, whereby αS aggregates are a major constituent of Lewy bodies, a hallmark of these diseases. Despite the apparent link between αS and neurodegeneration, the exact physiological function as well as the events initiating pathology are still elusive. Extensive literature evidence suggests that αS is involved in regulating neurotransmission, a function attributed to its metamorphic character enabling the interaction with a number of presynaptic membranes, where the protein localises. Under physiological conditions, αS is present in a dynamic equilibrium between membrane-bound and cytosolic states. Understanding the subtle variations in the membrane binding modes in different biological contexts is crucial to elucidate the physiological behaviour of αS. Therefore, the first half of this PhD aims to characterise molecular interactions and structural conformations of αS upon association with various presynaptic membranes. The results indicate that cholesterol modulates the overall affinity of αS to synaptic-like vesicles (SL-SUV) by reducing the local membrane affinity in the region 65-97. This in return enhances vesicle-vesicle interactions via a previously reported double-anchor mechanism, which has important implication on synaptic vesicle clustering (chapter III). In addition, direct evidence highlights that the docking of SL-SUVs to the surface of the inner leaflet of the plasma membrane (IPM) via the double-anchor mechanism is driven by preferential binding modes of the protein to the different membranes. Further data reveals that changes in the PM lipid composition(s), commonly associated with neurodegenerative contexts, influence the binding affinity specifically of the non-amyloid component (NAC, residues 61-95) region (chapter IV). Overall, these results conclude that lipid compositions moder…
abstract: The aberrant aggregation of intrinsically disordered α-Synuclein (αS) is associated with Parkinson’s disease (PD) and other neurodegenerative diseases termed synucleopathies, whereby αS aggregates are a major constituent of Lewy bodies, a hallmark of these diseases. Despite the apparent link between αS and neurodegeneration, the exact physiological function as well as the events initiating pathology are still elusive. Extensive literature evidence suggests that αS is involved in regulating neurotransmission, a function attributed to its metamorphic character enabling the interaction with a number of presynaptic membranes, where the protein localises. Under physiological conditions, αS is present in a dynamic equilibrium between membrane-bound and cytosolic states. Understanding the subtle variations in the membrane binding modes in different biological contexts is crucial to elucidate the physiological behaviour of αS. Therefore, the first half of this PhD aims to characterise molecular interactions and structural conformations of αS upon association with various presynaptic membranes. The results indicate that cholesterol modulates the overall affinity of αS to synaptic-like vesicles (SL-SUV) by reducing the local membrane affinity in the region 65-97. This in return enhances vesicle-vesicle interactions via a previously reported double-anchor mechanism, which has important implication on synaptic vesicle clustering (chapter III). In addition, direct evidence highlights that the docking of SL-SUVs to the surface of the inner leaflet of the plasma membrane (IPM) via the double-anchor mechanism is driven by preferential binding modes of the protein to the different membranes. Further data reveals that changes in the PM lipid composition(s), commonly associated with neurodegenerative contexts, influence the binding affinity specifically of the non-amyloid component (NAC, residues 61-95) region (chapter IV). Overall, these results conclude that lipid compositions moder…
author: Man, Wing
language: eng
keywords: Parkinson's disease, α-synuclein, Nuclear Magnetic Resonance, Protein aggregation, Thioflavin T
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2022-02-02
date modified: 2026-07-22T22:24:13Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.85753