Journal article 370 views
Brain cholesterol metabolites cause significant neurodegeneration in human iPSC-derived neurons
Yuqing Feng 
,
Bismoy Mazumder,
Tasuku Konno,
Ernestine Hui,
Marius Brockhoff,
Valentina Davi,
Meng Lu,
Edward Ward,
Amberley Stephens,
Wenyue Dai,
Ana Fernandez-Villegas,
Giuliana Fusco,
Mohsen Ali Asgari,
Edward Avezov,
Alfonso De Simone,
Yuqin Wang ,
William Griffiths ,
Clemens Kaminski ,
Gabriele Kaminski Schierle ,
Mohsen Ali Asgari
,
Bismoy Mazumder,
Tasuku Konno,
Ernestine Hui,
Marius Brockhoff,
Valentina Davi,
Meng Lu,
Edward Ward,
Amberley Stephens,
Wenyue Dai,
Ana Fernandez-Villegas,
Giuliana Fusco,
Mohsen Ali Asgari,
Edward Avezov,
Alfonso De Simone,
Yuqin Wang ,
William Griffiths ,
Clemens Kaminski ,
Gabriele Kaminski Schierle ,
Mohsen Ali Asgari
bioRxiv
Swansea University Authors:
Yuqin Wang , William Griffiths , Mohsen Ali Asgari
Full text not available from this repository: check for access using links below.
DOI (Published version): 10.1101/2025.06.10.656594
Abstract
Disrupted cholesterol metabolism is increasingly recognised as a contributing factor in neurodegeneration; however, the specific effects of key brain-derived cholesterol metabolites, 24S-hydroxycholesterol (24S-HC) and 27-hydroxycholesterol (27-HC), remain poorly understood. Using human iPSC-derived...
| Published in: | bioRxiv |
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| Published: |
Cold Spring Harbor Laboratory
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa69790 |
| Abstract: |
Disrupted cholesterol metabolism is increasingly recognised as a contributing factor in neurodegeneration; however, the specific effects of key brain-derived cholesterol metabolites, 24S-hydroxycholesterol (24S-HC) and 27-hydroxycholesterol (27-HC), remain poorly understood. Using human iPSC-derived i3 cortical neurons, we demonstrate that both 24S-HC and 27-HC significantly impair neuronal calcium signalling by elevating resting calcium levels, reducing spike amplitude, and disrupting network synchrony. These functional deficits are accompanied by widespread organelle dysfunction. Both oxysterols induce mitochondrial fragmentation, decrease spare respiratory capacity, and impair lysosomal degradation. Notably, 27-HC uniquely triggers lysosomal swelling and membrane permeabilisation. Additional signs of cellular stress, including axonal swellings and elevated endoplasmic reticulum calcium levels, were also observed. Furthermore, both 24S-HC and 27-HC were found to directly interact with alpha-synuclein (aSyn), promoting its accumulation in cellular models. In contrast, cholesterol itself had minimal impact, highlighting the distinct toxicity of its hydroxylated metabolites. Together, these findings reveal a mechanistic link between oxysterol accumulation and neuronal dysfunction, supporting the hypothesis that elevated levels of 24S-HC and 27-HC, commonly observed in Parkinson’s and Alzheimer’s disease, may actively drive neurodegenerative processes. Targeting oxysterol metabolism may therefore represent a promising therapeutic avenue for intervention in neurodegenerative disorders. |
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| Item Description: |
Preprint article before certification by peer review. |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
MR/X012387/1
BB/S019588/1 |