MSACL 2025 Abstract

Lipid Dysregulation in an ALS Drosophila Model: Insights from Time-of-Flight Secondary Ion Mass Spectrometry

Hyun Kyong Shon(1), Minh Uyen Thi Le(1), Jin Gyeong Son(1), Jeong Hyang Park(2), Chang Geon Chung(2), Sung Bae Lee(2), Tae Geol Lee(1)
(1) Korea Research Institute of Standards and Science (KRISS), Daejeon, South Korea (2) Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea

Hyunkyong Shon, Daejeon, South Korea (Presenter) Korea Research Institute of Standards and Science

Presenter Bio: Hyun Kyong Shon is a Principal Research Engineer at the Korea Research Institute of Standards and Science (KRISS). Her research focuses on mass spectrometry, particularly time-of-flight secondary ion mass spectrometry (ToF-SIMS), to conduct mass spectrometry-based imaging of various biological samples, such as brain, eye, kidney, and liver. Through this approach, she studies changes in metabolites and lipids to identify disease-related biomarkers.

Relevant Financial Disclosures (within past 24 months, reported on Aug 10, 2025) No relevant financial relationship(s) to disclose. Conflict mitigation NOT REQUIRED.

INTRODUCTION:
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron loss. The expansion of GGGGCC (G4C2) hexanucleotide repeats in the C9orf72 gene is the most common genetic cause of ALS. Lipid metabolism dysfunction has been implicated in ALS pathogenesis, but its early-stage dynamics remain poorly understood. This study applies time-of-flight secondary ion mass spectrometry (ToF-SIMS) to an ALS Drosophila model to investigate lipid alterations and their role in disease progression.

OBJECTIVES: This study aims to analyze the spatiotemporal changes in lipid composition in the brains of ALS Drosophila models. Additionally, we seek to determine whether specific lipid dysregulations occur before the onset of motor dysfunction. Furthermore, we aim to identify genetic factors related to lipid metabolism that contribute to ALS pathology.

METHODS: Drosophila expressing (G4C2)36 repeats in the C9orf72 gene were used as an ALS model. ToF-SIMS was employed to map lipid distributions in Drosophila heads at different disease stages (days 1, 3, 5, and 9). Principal component analysis (PCA) was conducted to identify key lipid alterations. Genetic screening using RNAi knockdown of lipid regulatory genes was performed to assess their effects on lipid profiles and neurodegeneration.

RESULTS: ToF-SIMS analysis revealed a significant increase in fatty acids, triacylglycerols, and ceramides in ALS model flies by day 5, preceding observable motor dysfunction at day 10. These lipids accumulated primarily in the fat body regions surrounding the brain. Genetic screening identified FATP1 and ACBP as key regulators of lipid alterations, with their knockdown reducing retinal degeneration and restoring lipid homeostasis. PCA confirmed that FATP1 and ACBP knockdowns resulted in lipid profiles similar to control flies, suggesting their role in ALS pathology.

CONCLUSION: Our study demonstrates that lipid dysregulation occurs early in ALS progression, prior to clinical symptoms. ToF-SIMS provides high-resolution spatial analysis of lipid alterations, revealing potential biomarkers for early-stage ALS. FATP1 and ACBP emerge as key contributors to lipid dysregulation, offering new targets for therapeutic intervention. These findings enhance our understanding of ALS pathogenesis and highlight the importance of lipid metabolism in neurodegeneration.