Identification and validation of Atp5f1c in CD4⁺ T cell as a hub protein in Parkinson's disease

Parkinson's disease (PD) is an age-related and progressive neurodegenerative disease. Growing evidences indicate that CD4⁺ T cell dysfunction plays an essential role in the progress of PD. Here, in LPS-induced PD mice, we isolated midbrain CD4⁺ T cell and peripheral CD4⁺ T cell to perform proteomics, and then screened a total of 167 co-expression proteins via integrated bioinformatics analysis. In addition, the subcellular localization, GO analysis, KEGG pathways and protein-protein interaction of 167 co-expression proteins were assessed. Furthermore, GeneMANIA searched the hub proteins and their co-expression genes and found 13 overlapping hub proteins, including Ndufa3, Cox5b, Mrpl21, Ndufab1, Idh3g, Ndufb7, Cyc1, Cisd1, Atp5f1c, Sdhc, Ndufb9, Mtnd1 and Mrpl17. Next, GO analysis and KEGG analysis of the 13 overlapping hub proteins were also exhibited. Further analysis identified that 4 hub proteins (Idh3g, Cisd1, Atp5f1c and Mtnd1) were downregulated both in midbrain and peripheral CD4⁺ T cell from proteomics. Identification and rescue experiment analysis showed that only Atp5f1c was decreased in LPS- and 6-OHDA-induced PD mice and dopamine (DA) neuronal loss and ATP production decrease were disappeared after Atp5f1c over-expression/Atp5f1c reinfusion both in vivo and in vitro. In conclusion, Atp5f1c was verified as a potential CD4⁺ T cell-related hub protein for PD.