The paper shows that astrocytic FABP5 is upregulated in MSA and, upon uptake of α-synuclein PFFs, drives TNFα-dependent inflammation and ferroptotic lipid peroxidation that depletes GPX3 and causes non-cell-autonomous oligodendrocyte death, while Fabp5 silencing rescues oligodendrocytes.

Although centered on MSA, the study defines an actionable astrocyte-mediated pathway (FABP5 → TNFα → ferroptosis/GPX3 loss) linking α-synuclein pathology to glial-driven degeneration, highlighting targets and modalities (FABP5 inhibition, TNF modulation, ferroptosis/GPX3-directed therapies) with…

Multiple system atrophy (MSA) is a fatal α-synucleinopathy characterized by progressive parkinsonism, cerebellar ataxia, and autonomic dysfunction. While white matter degeneration is a pathological hallmark, the molecular mechanisms driving neuroinflammation and oligodendrocyte loss remain poorly understood. Here, we identify astrocytic fatty acid-binding protein 5 (FABP5) as a critical mediator of this non-cell-autonomous injury through a multi-dimensional study involving human tissues, transgenic mice, and in vitro models. Transcriptomic profiling of MSA cerebellar white matter revealed a robust activation of inflammatory and ferroptotic pathways, with FABP5 upregulation strongly correlated with these pathogenic signatures (GSVA). We confirmed that FABP5 is upregulated in reactive astrocytes in the PLP-α-syn mouse model. Critically, using an MSA-specific α-synuclein (α-syn) pre-formed fibrils (PFFs) model, we demonstrate that PFFs uptake directly triggers FABP5-dependent inflammation and lipid peroxidation in astrocytes, recapitulating the phenotype observed with LPS stimulation. Mechanistically, we show that astrocytic FABP5 drives a TNF-α-mediated paracrine assault that depletes the antioxidant enzyme GPX3 and triggers apoptosis in neighboring oligodendrocytes. Importantly, silencing astrocytic Fabp5 effectively rescued oligodendrocytes from this oxidative injury and cell death. These findings establish astrocytic FABP5 as a central regulator linking glial inflammation to oligodendrocyte susceptibility, highlighting it as a promising therapeutic target for MSA.