Griffiths Lauren, Hawkins Kristen, Yutuc Eylan, Angelini Roberto, Fosuah Racheal, Pacciarini Manuela, Dickson Alison, Robertson Neil, Childs Laura, Loveless Samantha, Tallantyre Emma, Griffiths William J, Wang Yuqin, Howell Owain W
Institute of Life Sciences 1, Faculty of Medicine, Health and Life Sciences, Swansea University, Swansea, UK.
Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Brain Pathol. 2025 Sep;35(5):e70001. doi: 10.1111/bpa.70001. Epub 2025 Mar 5.
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.
多发性硬化症（MS）中残疾状况的恶化与神经退行性变有关。胆固醇稳态对正常脑功能至关重要。CYP46A1对脑胆固醇周转至关重要，在某些神经退行性疾病中表达降低，是一个潜在的神经保护靶点。我们假设CYP46A1在MS脑内表达下调，并与胆固醇失衡有关。对一个全女性MS队列（n = 32，平均年龄 = 33岁）中匹配的血浆和脑脊液（CSF）进行了甾醇的质谱分析。在基线和随访时记录残疾状况。对MS脑组织样本（n = 11；7名女性；年龄38 - 67岁；10例继发进展型MS，1例原发进展型MS；病程：13 - 49年）和对照样本（n = 8；3名女性；年龄41 - 68岁）使用质谱分析病理区域，并使用原位杂交分析RNA表达。患者群体中CSF中25 - 羟基胆固醇、27 - 羟基胆固醇和3β - 羟基胆甾烯酸的显著失调与基线和随访时的残疾状况相关。在脑组织中，白质病变中观察到胆固醇、24S - 羟基胆固醇和24S,25 - 环氧胆固醇减少（p < 0.05），这与CYP46A1活性有关。CYP46A1表达在神经元中富集，与对照组相比，MS灰质病变和非病变区域中CYP46A1表达降低（p < 0.01）。MS中胆固醇代谢失调，且与神经元特异性CYP46A1表达降低有关。调节CYP46A1这一可成药靶点可能对进展型MS有益。
