Deciphering Ferroptosis-Related Astrocyte Subpopulations and Diagnostic Biomarkers in Parkinson’s Disease through RNA Transcriptomics

Parkinson`s disease (PD) is the second most prevalent neurodegenerative disorder, and increasing evidence indicates that glial activation plays a significant role in ferroptosis and the subsequent neurodegeneration. In this study, we aimed to identify ferroptosis-related astrocytes exhibiting elevated inflammation scores in PD patients. The single-cell and bulk RNA transcriptomic profiles of PD samples were collected from the Gene Expression Omnibus database. We characterized seven cell types in the substantia nigra region of PD and normal samples, and discovering that astrocytes from the PD group interacted with microglia and oligodendrocytes. Furthermore, we identified five distinct astrocyte subpopulations: Astro-C0, -C1, -C2, -C3, and -C4. The Astro-C1 subpopulation was found to be correlated with ferroptosis. Trajectory analysis revealed that the Astro-C4 subpopulation clustered at the anterior end of the differentiation trajectory, followed by a gradual transition to the Astro-C0 and Astro-C1 subpopulations. Additionally, we identified ferroptosis-related genes (NEAT1, HSPB1, HSPA5, and ATF4) within the Astro-C1 subpopulation and noting that NEAT1, HSPB1, and HSPA5 exhibited diagnostic potential for PD. Our findings indicated that lipopolysaccharide (LPS) treatment exacerbated astrocyte ferroptosis, as evidenced by elevated levels of Fe2 + , MDA, lipid ROS, and intracellular ROS, along with decreased MMP in PD. Moreover, the high expression of NEAT1 and low levels of HSPB1, ATF4, and HSPA5, might serve as a diagnostic indicator of ferroptosis in PD. Our study revealed that inflammation might exacerbate astrocyte ferroptosis. Additionally, NEAT1, HSPB1, and HSPA5 might serve as diagnostic markers for ferroptosis in PD.