Unravelling the pathogenic role of iron dysregulation in MSA

Multiple system atrophy (MSA) is a rare devastating brain disease, leading to severe movement difficulties and, ultimately, death. It shares some similarities with Parkinsons disease (PD), but it progresses much faster and affects different brain cells. In MSA, abnormal aggregates of the protein alpha-synuclein build up inside support cells of the brain known as oligodendrocytes. However, it is not yet fully understood how and why alpha-synuclein accumulates in oligodendrocytes or why MSA progresses more rapidly than PD. One possible trigger is iron. The brains of people with MSA contain unusually high amounts of iron, even more than those with PD. Previous research has shown that iron can trigger alpha-synuclein aggregation, and that these aggregates, in turn, can cause further iron accumulation, creating a vicious cycle that may worsen the disease. Interestingly, oligodendrocytes naturally contain the highest iron levels of any brain cell, making them particularly vulnerable. Our early research in mice with MSA-like symptoms shows that iron accumulation occurs before neuronal loss in the brain areas affected by this disorder and continues to build up as the disease progresses. However, it remains unclear whether this iron dysregulation directly contributes to brain cell loss or if it is merely a secondary event resulting from other pathological processes. In this project, we aim to uncover how iron imbalance contributes to MSA. To better understand this, we will use a specialized mouse model of MSA that mimics many of the diseases key features, including movement difficulties, alpha-synuclein accumulation, neuronal loss and neuroinflammation. By studying these mice at different stages of the disease, we will track how iron levels change in different brain areas and cell types over time and examine their relationship with neurodegeneration and worsening symptoms. We will combine behavioral tests, which assess movement abilities, with advanced techniques to analyse iron distribution, alpha-synuclein pathology, and the extent of brain cell damage. Additionally, we will investigate whether iron-related changes in the blood and other body fluids could serve as early biomarkers of disease progression. Our research will help to understand how iron disruption affects MSA differently from PD. It could also open doors to new treatment strategies and help identify biological markers that might be used in future clinical trials. Researchers leading this study: Antonio Heras Garvin, Nadia Stefanova.