Oligodendrocyte-astrocyte crosstalk in Parkinson’s disease mediates neuronal ferroptosis via the FGF signaling pathway

Abstract

Parkinson’s disease (PD), as a neurodegenerative disorder, is characterized primarily by damage to the central nervous system, accompanied by astrocyte dysfunction and the activation of ferroptosis. Recent studies have shown that oligodendrocytes also exhibit functional abnormalities in the brains of PD patients and are involved in the ferroptotic process. However, it remains unclear whether there is an interaction between oligodendrocytes and astrocytes and how they induce neuronal ferroptosis. Here, we employed single-nucleus sequencing and spatial transcriptomics to characterize the intercellular communication network between oligodendrocytes and astrocytes in the PD environment. Among these, astrocytes are the primary recipients of signals sent by oligodendrocytes in the FGF (Fibroblast growth factors) signaling pathway. In PD, the communication intensity is weakened, involving FGF1 and FGF9 and their receptors FGFR1, FGFR2, and FGFR3. Subsequently, we further validated the significant activation of mitochondrial oxidative phosphorylation processes within oligodendrocytes and astrocytes in PD mice, and that astrocytes might also involve the interaction of Mt1 and Ca²⁺. Additionally, we demonstrated a significant reduction in the number of DA neurons in the SN region and a notable activation of ferroptosis, alongside a significant decrease in the antioxidant pathway NRF2/SLC7A11/GPX4. In summary, our data elucidate that ferroptosis in the midbrain SN region preferentially occurs in astrocytes under the dysregulation of oligodendrocytes, leading to ferroptosis in DA neurons. Thus, our study highlights the crucial role of oligodendrocyte-astrocyte crosstalk in driving neuronal inactivation and inflammatory expansion in PD.