Ferroptosis in Multiple Sclerosis: A Double-Edged Sword in Neuroinflammation and Neurodegeneration
Multiple Sclerosis (MS), a chronic autoimmune disorder affecting the central nervous system (CNS), is characterized by neuroinflammation and neurodegeneration. A recent study by Wu et al., published in Journal of Cellular and Molecular Medicine (2024), sheds light on the role of ferroptosis, a unique form of iron-dependent cell death, in the pathogenesis of MS. By leveraging advanced multi-omics techniques, the study provides compelling evidence for ferroptosis as a dual contributor to neuroimmunity and neurodegeneration, while proposing its potential as a novel therapeutic target.
What is Ferroptosis?
Ferroptosis is distinct from apoptosis and necrosis, characterized by iron-dependent lipid peroxidation and mitochondrial shrinkage. While its role in neurodegenerative diseases like Alzheimer’s and Parkinson’s has been explored, its impact on MS was unclear until this study.
The Study Design: Multi-Omics in Action
The researchers employed single-nucleus RNA sequencing (snRNA-seq), spatial transcriptomics, and spatial proteomics to investigate ferroptosis in MS. Data from white and grey matter lesions of MS patients were analyzed alongside peripheral blood (PB) and cerebrospinal fluid (CSF) samples. A computational ferroptosis score was developed to quantify the activity of ferroptosis-related genes.
Key Findings
Ferroptosis in White Matter Lesions
MS lesions showed elevated ferroptosis scores, particularly at the edges of active lesions. This aligns with iron redistribution patterns observed in imaging studies.
Among immune cells, microglia and monocyte-derived cells exhibited the highest ferroptosis scores, emphasizing their role in iron metabolism and inflammatory responses.
Ferroptosis and Phagocyte Activation
Activated microglia and monocyte-derived macrophages demonstrated increased ferroptosis scores. These cells also displayed enhanced antigen presentation and T-cell activation capabilities, linking ferroptosis to immune dysregulation in MS.
Cortical Neurodegeneration
In the grey matter, cortical neurons exhibited significantly higher ferroptosis scores, particularly excitatory neurons in specific cortical layers. This may contribute to cognitive impairments and neurodegeneration seen in MS.
Spatial Co-Localization of Ferroptosis and Neurodegeneration
Spatial transcriptomics revealed that regions with high ferroptosis scores coincided with severe neurodegeneration, underscoring a potential causal relationship.
Ferroptosis as a Biomarker
A machine learning model based on 24 ferroptosis-related genes effectively distinguished MS patients from controls, with an area under the curve (AUC) exceeding 0.7 across multiple datasets. This highlights the potential for ferroptosis markers in MS diagnosis and prognosis.
Implications for Therapy
The findings suggest that ferroptosis contributes to MS pathogenesis through dual roles:
Promoting immune inflammation via phagocyte activation.
Driving neuronal damage in the CNS.
Therapeutic interventions targeting ferroptosis, such as inhibitors of lipid peroxidation or iron chelation therapies, may hold promise for mitigating both inflammation and neurodegeneration in MS.
Conclusion
Wu et al.’s study advances our understanding of MS by unveiling the intricate involvement of ferroptosis in both neuroimmunity and neurodegeneration. Through state-of-the-art multi-omics, it not only identifies ferroptosis as a key player in MS but also sets the stage for innovative diagnostic and therapeutic strategies. As we unravel the complexities of ferroptosis in MS, this research highlights a path toward precision medicine in neuroimmunological diseases.
References:
Mitani, T., Isikay, S., Gezdirici, A., Gulec, E. Y., Punetha, J., Fatih, J. M., ... & Pehlivan, D. (2021). High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population. The American Journal of Human Genetics, 108(10), 1981-2005.
