Sterol imbalances and cholesterol‐24‐hydroxylase dysregulation is linked to the underlying progression of multiple sclerosis

Griffiths, Lauren; Hawkins, Kristen; Yutuc, Eylan; Angelini, Roberto; Fosuah, Racheal; Pacciarini, Manuela; Dickson, Alison; Robertson, Neil; Childs, Laura; Loveless, Samantha; Tallantyre, Emma; Griffiths, William; Wang, Yuqin; Howell, Owain

doi:10.1111/bpa.70001

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Sterol imbalances and cholesterol‐24‐hydroxylase dysregulation is linked to the underlying progression of multiple sclerosis

Lauren Griffiths, Kristen Hawkins, Eylan Yutuc

, Roberto Angelini

, Racheal Fosuah, Manuela Pacciarini, Alison Dickson, Neil Robertson, Laura Childs, Samantha Loveless

, Emma Tallantyre, William Griffiths

, Yuqin Wang

, Owain Howell

Brain Pathology, Start page: e70001

Swansea University Authors: Lauren Griffiths, Kristen Hawkins, Eylan Yutuc , Roberto Angelini , William Griffiths , Yuqin Wang , Owain Howell

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DOI (Published version): 10.1111/bpa.70001

Abstract

Disability worsening in multiple sclerosis (MS) is linked to neurodegeneration. Cholesterol homeostasis is essential for normal brain function. CYP46A1, crucial for brain cholesterol turnover and reduced in some neurodegenerative diseases, is a potential neuroprotective target. We hypothesized that...

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Published in:	Brain Pathology
ISSN:	1015-6305 1750-3639
Published:	Wiley 2025
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa68901

first_indexed	2025-02-17T12:34:53Z
last_indexed	2025-08-07T08:09:26Z
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Cholesterol homeostasis is essential for normal brain function. CYP46A1, crucial for brain cholesterol turnover and reduced in some neurodegenerative diseases, is a potential neuroprotective target. We hypothesized that CYP46A1 is downregulated in MS brains and linked to cholesterol dysbalance. Mass spectrometric analysis of sterols was performed from matched plasma and cerebrospinal fluid (CSF) in an all-female MS cohort (n = 32, mean age = 33). Disability status was recorded at baseline and follow-up. MS brain tissue samples (n = 11; 7 females; ages 38–67; 10 Secondary Progressive MS, 1 Primary Progressive MS; Disease Duration: 13–49 years) and control samples (n = 8; 3 females; ages 41–68) analysed for pathological regions using mass spectrometry and RNA expression using in-situ hybridization. Significant dysregulation in 25-hydroxycholesterol, 27-hydroxycholesterol and 3β-hydroxycholestenoic acid in CSF correlated with disability at baseline and follow-up in the patient population. In brain tissue, reduced cholesterol, 24S-hydroxycholesterol and 24S,25-epoxycholesterol were observed in white matter lesions (p < 0.05), linked to CYP46A1 activity. CYP46A1 expression was enriched in neurons, with reductions in MS grey matter lesions and non-lesions compared to controls (p < 0.01). Cholesterol metabolism is dysregulated in MS and is associated with reduced neuron-specific CYP46A1 expression. Modulating CYP46A1, a druggable target, may benefit progressive MS.</abstract><type>Journal Article</type><journal>Brain Pathology</journal><volume>0</volume><journalNumber/><paginationStart>e70001</paginationStart><paginationEnd/><publisher>Wiley</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>1015-6305</issnPrint><issnElectronic>1750-3639</issnElectronic><keywords>cholesterol, cholesterol-24-hydroxylase (CYP46A1), mass spectrometry, multiple sclerosis (MS), neurodegeneration, progression, sterols</keywords><publishedDay>5</publishedDay><publishedMonth>3</publishedMonth><publishedYear>2025</publishedYear><publishedDate>2025-03-05</publishedDate><doi>10.1111/bpa.70001</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>SU Library paid the OA fee (TA Institutional Deal)</apcterm><funders>This work was supported by the UK MS Society [grant 94], the Research Wales Innovation Fund, the BRAIN Unit Infrastructure Award (Grant no. UA05; funded by Welsh Government through Health and Care Research Wales), MRC Impact Acceleration Account, BBSRC grant no. BB/N015932/1, BB/S019588/1, BB/L001942/1, BB/T018542/1, and by the European Union, as part of the Welsh Government-funded Academic Expertise for Business project.</funders><projectreference/><lastEdited>2025-08-06T11:11:36.8805323</lastEdited><Created>2025-02-17T12:27:10.2669109</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Lauren</firstname><surname>Griffiths</surname><order>1</order></author><author><firstname>Kristen</firstname><surname>Hawkins</surname><order>2</order></author><author><firstname>Eylan</firstname><surname>Yutuc</surname><orcid>0000-0001-9971-1950</orcid><order>3</order></author><author><firstname>Roberto</firstname><surname>Angelini</surname><orcid>0000-0001-5136-5921</orcid><order>4</order></author><author><firstname>Racheal</firstname><surname>Fosuah</surname><order>5</order></author><author><firstname>Manuela</firstname><surname>Pacciarini</surname><order>6</order></author><author><firstname>Alison</firstname><surname>Dickson</surname><order>7</order></author><author><firstname>Neil</firstname><surname>Robertson</surname><order>8</order></author><author><firstname>Laura</firstname><surname>Childs</surname><order>9</order></author><author><firstname>Samantha</firstname><surname>Loveless</surname><orcid>0000-0002-5124-4115</orcid><order>10</order></author><author><firstname>Emma</firstname><surname>Tallantyre</surname><order>11</order></author><author><firstname>William</firstname><surname>Griffiths</surname><orcid>0000-0002-4129-6616</orcid><order>12</order></author><author><firstname>Yuqin</firstname><surname>Wang</surname><orcid>0000-0002-3063-3066</orcid><order>13</order></author><author><firstname>Owain</firstname><surname>Howell</surname><orcid>0000-0003-2157-9157</orcid><order>14</order></author></authors><documents><document><filename>68901__33807__b65de2d2576d4d1b83e05845657512df.pdf</filename><originalFilename>68901.VOR.pdf</originalFilename><uploaded>2025-03-13T13:32:59.4325011</uploaded><type>Output</type><contentLength>2004465</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>© 2025 The Author(s). 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spelling	2025-08-06T11:11:36.8805323 v2 68901 2025-02-17 Sterol imbalances and cholesterol‐24‐hydroxylase dysregulation is linked to the underlying progression of multiple sclerosis 8811c280da03bf66352d97f756e91ae1 Lauren Griffiths Lauren Griffiths true false e49e8a552ec24b278bee246db3f8d8a8 Kristen Hawkins Kristen Hawkins true false 99332f073ce913a9b7d8b6441b17516d 0000-0001-9971-1950 Eylan Yutuc Eylan Yutuc true false 6405b7880498750d41c93c6ff89cff96 0000-0001-5136-5921 Roberto Angelini Roberto Angelini true false 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 58c995486fc93a242b987640b692db8c 0000-0003-2157-9157 Owain Howell Owain Howell true false 2025-02-17 MEDS Disability worsening in multiple sclerosis (MS) is linked to neurodegeneration. Cholesterol homeostasis is essential for normal brain function. CYP46A1, crucial for brain cholesterol turnover and reduced in some neurodegenerative diseases, is a potential neuroprotective target. We hypothesized that CYP46A1 is downregulated in MS brains and linked to cholesterol dysbalance. Mass spectrometric analysis of sterols was performed from matched plasma and cerebrospinal fluid (CSF) in an all-female MS cohort (n = 32, mean age = 33). Disability status was recorded at baseline and follow-up. MS brain tissue samples (n = 11; 7 females; ages 38–67; 10 Secondary Progressive MS, 1 Primary Progressive MS; Disease Duration: 13–49 years) and control samples (n = 8; 3 females; ages 41–68) analysed for pathological regions using mass spectrometry and RNA expression using in-situ hybridization. Significant dysregulation in 25-hydroxycholesterol, 27-hydroxycholesterol and 3β-hydroxycholestenoic acid in CSF correlated with disability at baseline and follow-up in the patient population. In brain tissue, reduced cholesterol, 24S-hydroxycholesterol and 24S,25-epoxycholesterol were observed in white matter lesions (p < 0.05), linked to CYP46A1 activity. CYP46A1 expression was enriched in neurons, with reductions in MS grey matter lesions and non-lesions compared to controls (p < 0.01). Cholesterol metabolism is dysregulated in MS and is associated with reduced neuron-specific CYP46A1 expression. Modulating CYP46A1, a druggable target, may benefit progressive MS. Journal Article Brain Pathology 0 e70001 Wiley 1015-6305 1750-3639 cholesterol, cholesterol-24-hydroxylase (CYP46A1), mass spectrometry, multiple sclerosis (MS), neurodegeneration, progression, sterols 5 3 2025 2025-03-05 10.1111/bpa.70001 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University SU Library paid the OA fee (TA Institutional Deal) This work was supported by the UK MS Society [grant 94], the Research Wales Innovation Fund, the BRAIN Unit Infrastructure Award (Grant no. UA05; funded by Welsh Government through Health and Care Research Wales), MRC Impact Acceleration Account, BBSRC grant no. BB/N015932/1, BB/S019588/1, BB/L001942/1, BB/T018542/1, and by the European Union, as part of the Welsh Government-funded Academic Expertise for Business project. 2025-08-06T11:11:36.8805323 2025-02-17T12:27:10.2669109 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Lauren Griffiths 1 Kristen Hawkins 2 Eylan Yutuc 0000-0001-9971-1950 3 Roberto Angelini 0000-0001-5136-5921 4 Racheal Fosuah 5 Manuela Pacciarini 6 Alison Dickson 7 Neil Robertson 8 Laura Childs 9 Samantha Loveless 0000-0002-5124-4115 10 Emma Tallantyre 11 William Griffiths 0000-0002-4129-6616 12 Yuqin Wang 0000-0002-3063-3066 13 Owain Howell 0000-0003-2157-9157 14 68901__33807__b65de2d2576d4d1b83e05845657512df.pdf 68901.VOR.pdf 2025-03-13T13:32:59.4325011 Output 2004465 application/pdf Version of Record true © 2025 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License (CC BY). true eng http://creativecommons.org/licenses/by/4.0/
title	Sterol imbalances and cholesterol‐24‐hydroxylase dysregulation is linked to the underlying progression of multiple sclerosis
spellingShingle	Sterol imbalances and cholesterol‐24‐hydroxylase dysregulation is linked to the underlying progression of multiple sclerosis Lauren Griffiths Kristen Hawkins Eylan Yutuc Roberto Angelini William Griffiths Yuqin Wang Owain Howell
title_short	Sterol imbalances and cholesterol‐24‐hydroxylase dysregulation is linked to the underlying progression of multiple sclerosis
title_full	Sterol imbalances and cholesterol‐24‐hydroxylase dysregulation is linked to the underlying progression of multiple sclerosis
title_fullStr	Sterol imbalances and cholesterol‐24‐hydroxylase dysregulation is linked to the underlying progression of multiple sclerosis
title_full_unstemmed	Sterol imbalances and cholesterol‐24‐hydroxylase dysregulation is linked to the underlying progression of multiple sclerosis
title_sort	Sterol imbalances and cholesterol‐24‐hydroxylase dysregulation is linked to the underlying progression of multiple sclerosis
author_id_str_mv	8811c280da03bf66352d97f756e91ae1 e49e8a552ec24b278bee246db3f8d8a8 99332f073ce913a9b7d8b6441b17516d 6405b7880498750d41c93c6ff89cff96 3316b1d1b524be1831790933eed1c26e c92729b58622f9fdf6a0e7d8f4ce5081 58c995486fc93a242b987640b692db8c
author_id_fullname_str_mv	8811c280da03bf66352d97f756e91ae1_*_Lauren Griffiths e49e8a552ec24b278bee246db3f8d8a8__Kristen Hawkins 99332f073ce913a9b7d8b6441b17516d__Eylan Yutuc 6405b7880498750d41c93c6ff89cff96__Roberto Angelini 3316b1d1b524be1831790933eed1c26e__William Griffiths c92729b58622f9fdf6a0e7d8f4ce5081__Yuqin Wang 58c995486fc93a242b987640b692db8c_**_Owain Howell
author	Lauren Griffiths Kristen Hawkins Eylan Yutuc Roberto Angelini William Griffiths Yuqin Wang Owain Howell
author2	Lauren Griffiths Kristen Hawkins Eylan Yutuc Roberto Angelini Racheal Fosuah Manuela Pacciarini Alison Dickson Neil Robertson Laura Childs Samantha Loveless Emma Tallantyre William Griffiths Yuqin Wang Owain Howell
format	Journal article
container_title	Brain Pathology
container_volume	0
container_start_page	e70001
publishDate	2025
institution	Swansea University
issn	1015-6305 1750-3639
doi_str_mv	10.1111/bpa.70001
publisher	Wiley
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
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hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description	Disability worsening in multiple sclerosis (MS) is linked to neurodegeneration. Cholesterol homeostasis is essential for normal brain function. CYP46A1, crucial for brain cholesterol turnover and reduced in some neurodegenerative diseases, is a potential neuroprotective target. We hypothesized that CYP46A1 is downregulated in MS brains and linked to cholesterol dysbalance. Mass spectrometric analysis of sterols was performed from matched plasma and cerebrospinal fluid (CSF) in an all-female MS cohort (n = 32, mean age = 33). Disability status was recorded at baseline and follow-up. MS brain tissue samples (n = 11; 7 females; ages 38–67; 10 Secondary Progressive MS, 1 Primary Progressive MS; Disease Duration: 13–49 years) and control samples (n = 8; 3 females; ages 41–68) analysed for pathological regions using mass spectrometry and RNA expression using in-situ hybridization. Significant dysregulation in 25-hydroxycholesterol, 27-hydroxycholesterol and 3β-hydroxycholestenoic acid in CSF correlated with disability at baseline and follow-up in the patient population. In brain tissue, reduced cholesterol, 24S-hydroxycholesterol and 24S,25-epoxycholesterol were observed in white matter lesions (p < 0.05), linked to CYP46A1 activity. CYP46A1 expression was enriched in neurons, with reductions in MS grey matter lesions and non-lesions compared to controls (p < 0.01). Cholesterol metabolism is dysregulated in MS and is associated with reduced neuron-specific CYP46A1 expression. Modulating CYP46A1, a druggable target, may benefit progressive MS.
published_date	2025-03-05T05:26:43Z
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score	11.444299

Sterol imbalances and cholesterol‐24‐hydroxylase dysregulation is linked to the underlying progression of multiple sclerosis

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