Astrocytic FABP5 drives non-cell-autonomous oligodendrocyte injury in multiple system atrophy by promoting TNF signaling and ferroptotic stress

Wu, C.; Lin, J.; Chen, Y.; Takahashi, N.; Chen, Q.; Liu, B.; Dai, F.; Zhao, W.; Finkelstein, D. I.; Kawahata, I.; Fukunaga, K.; Cheng, A.

doi:10.1101/2025.11.08.687320

bioRxiv · 10.1101/2025.11.08.687320

Astrocytic FABP5 drives non-cell-autonomous oligodendrocyte injury in multiple system atrophy by promoting TNF signaling and ferroptotic stress

Wu, C.·Lin, J.·Chen, Y.·Takahashi, N.·Chen, Q.·Liu, B.·Dai, F.·Zhao, W.·Finkelstein, D. I.·Kawahata, I.·Fukunaga, K.·Cheng, A.

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Abstract

Multiple system atrophy (MSA) is a fatal -synucleinopathy characterized by progressive parkinsonism, cerebellar and autonomic dysfunction. Currently, the mechanisms driving cerebellar white matter neuroinflammation and degeneration in MSA are poorly understood. Here, we identified fatty acid-binding protein 5 (FABP5) as a key factor regulating cerebellar inflammation in MSA pathogenesis in a detailed study of human, mouse and cultured astrocytes. Firstly, transcriptomic profiling of human MSA cerebellar white matter revealed activation of pro-inflammatory and ferroptotic pathways, with FABP5 identified as a key pathway component that is upregulated. We confirmed that FABP5 is upregulated in reactive astrocytes in the PLP--syn transgenic mouse model, also in LPS-treated primary astrocytes. Fabp5 silencing suppressed TNF signaling, mitigated ferroptosis, and restored mitochondrial function. These findings suggest astrocytic FABP5 as a central intracellular regulator linking glial inflammation, ferroptosis, and mitochondrial injury. Overall, this mechanism suggests that FABP5 drives pathology mediated by astrocytes oligodendroglia in MSA, therefore representing a novel and promising therapeutic target.

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Wu, C., Lin, J., Chen, Y., Takahashi, N., Chen, Q., Liu, B., Dai, F., Zhao, W., Finkelstein, D. I., Kawahata, I., Fukunaga, K., Cheng, A.. 2025-11-10. Astrocytic FABP5 drives non-cell-autonomous oligodendrocyte injury in multiple system atrophy by promoting TNF signaling and ferroptotic stress. https://doi.org/10.1101/2025.11.08.687320

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