Isik Finula I, Fu YuHong, Pickford Russell, Cheng Qi, Yang Yue, Lewis Simon J G, Dzamko Nicolas, Halliday Glenda M, Kim Woojin Scott
Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia.
School of Medical Sciences, The University of Sydney, Sydney, NSW, Australia.
Mov Disord. 2025 May 23. doi: 10.1002/mds.30248.
Multiple system atrophy (MSA) is a neurodegenerative disease pathologically characterized by the presence of glial cytoplasmic inclusions (GCI) composed of α-synuclein aggregates. In Parkinson's disease, increases in monounsaturated fatty acids (MUFA) in phospholipid membranes promote α-synuclein binding, aggregation, and toxicity, and the inhibition of stearoyl-CoA desaturase (SCD), the enzyme responsible for synthesizing MUFA, alleviates α-synuclein toxicity. However, little is known about phospholipid MUFA or SCD in the context of MSA pathology.
To determine whether phospholipid MUFA and SCD levels are altered in MSA brain and related to α-synuclein pathology.
Phospholipid MUFA levels in the disease-affected motor cortex white matter (MWM) and disease-unaffected superior occipital cortex (SOC) of postmortem MSA and control brain were analyzed using liquid chromatography-mass spectrometry. Brain GCI, α-synuclein, and SCD were analyzed using immunofluorescence, Western blotting, and quantitative polymerase chain reaction (qPCR). Serum SCD was analyzed using ELISA.
MUFA in phosphatidic acid, phosphatidylcholine, and phosphatidylethanolamine were elevated in MSA MWM compared with control MWM by 3.9%, 8.8%, and 9.5%, respectively, whereas none were altered in SOC. MUFA were strongly associated with α-synuclein only in MWM. SCD mRNA and protein expression were decreased only in MSA MWM compared with control MWM.
These findings suggest a prevalence of MUFA dysregulation in specific regions of MSA brain, resulting in MUFA levels remaining high despite decreases in SCD expression. Our study has provided new insights into an unrecognized pathway in MSA and opened a new area of research for better understanding MSA pathogenesis. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
多系统萎缩（MSA）是一种神经退行性疾病，其病理特征是存在由α-突触核蛋白聚集体组成的胶质细胞胞质内含物（GCI）。在帕金森病中，磷脂膜中单不饱和脂肪酸（MUFA）的增加会促进α-突触核蛋白的结合、聚集和毒性，而抑制负责合成MUFA的硬脂酰辅酶A去饱和酶（SCD）可减轻α-突触核蛋白的毒性。然而，在MSA病理学背景下，关于磷脂MUFA或SCD的了解甚少。
确定MSA脑内磷脂MUFA和SCD水平是否改变以及是否与α-突触核蛋白病理学相关。
使用液相色谱-质谱分析法分析死后MSA患者和对照者大脑中受疾病影响的运动皮质白质（MWM）和未受疾病影响的枕叶上部皮质（SOC）中的磷脂MUFA水平。使用免疫荧光、蛋白质印迹法和定量聚合酶链反应（qPCR）分析脑内GCI、α-突触核蛋白和SCD。使用酶联免疫吸附测定法（ELISA）分析血清SCD。
与对照MWM相比，MSA MWM中磷脂酸、磷脂酰胆碱和磷脂酰乙醇胺中的MUFA分别升高了3.9%、8.8%和9.5%，而SOC中均未改变。仅在MWM中，MUFA与α-突触核蛋白密切相关。与对照MWM相比，仅MSA MWM中的SCD mRNA和蛋白表达降低。
这些发现表明MSA脑的特定区域存在MUFA失调，尽管SCD表达降低，但MUFA水平仍保持较高。我们的研究为MSA中一条未被认识的途径提供了新见解，并开辟了一个新的研究领域，以更好地理解MSA的发病机制。© 2025作者。《运动障碍》由Wiley Periodicals LLC代表国际帕金森和运动障碍协会出版。
