Dysregulation of Monounsaturated Fatty Acids is Related to α-Synuclein in Multiple System Atrophy.

BACKGROUND: 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. OBJECTIVES: To determine whether phospholipid MUFA and SCD levels are altered in MSA brain and related to α-synuclein pathology. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.