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.

Lewy body diseases (LBD), including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), are neurodegenerative disorders characterized by the intracellular aggregation and accumulation of α-Synuclein (αSyn), leading to neuronal death. Although these diseases primarily present with symptoms affecting the central nervous system (CNS), such as motor and cognitive impairment, increasing research suggests that their roots may be found in the gut. This review summarizes recent findings and key historical insights into the involvement of the gut in αSyn pathology. The topics covered include pathological observations in patients with LBD, animal models investigating the propagation of αSyn from the gut to the brain, intestinal inflammation, alterations in the gut microbiome, and the molecular mechanisms of αSyn pathology within enteric neurons. These topics are essential for understanding the involvement of the gut in αSyn pathology and provide foundational insights that may lead to future therapeutic applications.