Oxysterols in Neurodegeneration and the Influence of Presynaptic α-Synuclein Phosphorylation
type: CreativeWork
description: Neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) are marked by progressive neuronal dysfunction, often driven by protein misfolding and chronic cellular stress. Among the emerging contributors to these pathologies is disrupted cholesterol metabolism, particularly the accumulation of oxidised cholesterol derivatives known as oxysterols. Notably, 24S-hydroxycholesterol (24S-HC) and 27-hydroxycholesterol (27-HC) have been implicated in exacerbating neurodegenerative processes by modulating protein aggregation and increasing cellular vulnerability. However, the precise molecular and cellular mechanisms through which these oxysterols exert their effects remain insufficiently understood. In this study, we explored the role of oxysterols in protein aggregation and neuronal dysfunction, with a specific focus on alpha-synuclein (aSyn), a presynaptic protein centrally involved in PD pathology. Biophysical analyses revealed that both 24S-HC and 27-HC bind directly to aSyn with higher affinity than cholesterol. Interestingly, despite this binding, 27-HC does not alter the intrinsically disordered conformation of aSyn in solution. In cell-based models, exposure to either oxysterol led to increased intracellular aSyn levels. Moreover, we observed a reciprocal effect whereby extracellular aSyn enhanced oxysterol uptake and metabolism, pointing to a potential feedforward mechanism that could accelerate disease progression. To assess the broader functional consequences of oxysterol accumulation, we investigated their effects on human iPSC-derived neurons. Both 24S-HC and 27-HC impaired calcium signalling and disrupted neuronal network synchrony, reflecting compromised neuronal communication. At the subcellular level, oxysterols induced widespread organelle dysfunction, including impaired mitochondrial integrity, reduced lysosomal degradation capacity, and disturbed endoplasmic reticulum (ER) homeostasis. Notably, 27-HC uniquely caused lysosoma…
abstract: Neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) are marked by progressive neuronal dysfunction, often driven by protein misfolding and chronic cellular stress. Among the emerging contributors to these pathologies is disrupted cholesterol metabolism, particularly the accumulation of oxidised cholesterol derivatives known as oxysterols. Notably, 24S-hydroxycholesterol (24S-HC) and 27-hydroxycholesterol (27-HC) have been implicated in exacerbating neurodegenerative processes by modulating protein aggregation and increasing cellular vulnerability. However, the precise molecular and cellular mechanisms through which these oxysterols exert their effects remain insufficiently understood. In this study, we explored the role of oxysterols in protein aggregation and neuronal dysfunction, with a specific focus on alpha-synuclein (aSyn), a presynaptic protein centrally involved in PD pathology. Biophysical analyses revealed that both 24S-HC and 27-HC bind directly to aSyn with higher affinity than cholesterol. Interestingly, despite this binding, 27-HC does not alter the intrinsically disordered conformation of aSyn in solution. In cell-based models, exposure to either oxysterol led to increased intracellular aSyn levels. Moreover, we observed a reciprocal effect whereby extracellular aSyn enhanced oxysterol uptake and metabolism, pointing to a potential feedforward mechanism that could accelerate disease progression. To assess the broader functional consequences of oxysterol accumulation, we investigated their effects on human iPSC-derived neurons. Both 24S-HC and 27-HC impaired calcium signalling and disrupted neuronal network synchrony, reflecting compromised neuronal communication. At the subcellular level, oxysterols induced widespread organelle dysfunction, including impaired mitochondrial integrity, reduced lysosomal degradation capacity, and disturbed endoplasmic reticulum (ER) homeostasis. Notably, 27-HC uniquely caused lysosoma…
author: Feng, Yuqing
language: eng
keywords: Oxysterol, Neurodegeneration, α-Synuclein
license: https://www.repository.cam.ac.uk/bitstreams/21f8c573-d381-47eb-977a-69d00658d7bd/download
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2025-08-04
date modified: 2026-07-24T01:33:05Z
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.122342