Inhibition of abnormal C/EBPβ/α‐Syn signaling pathway through activation of Nrf2 ameliorates Parkinson's disease‐like pathology

Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs) in the brain. These LBs are primarily composed of α‐Synuclein (α‐Syn), which has aggregated. A recent report proposes that CCAAT/enhancer‐binding proteins β (C/EBPβ) may act as an age‐dependent transcription factor for α‐Syn, thereby initiating PD pathologies by regulating its transcription. Potential therapeutic approaches to address PD could involve targeting the regulation of α‐Syn by C/EBPβ. This study has revealed that Nrf2, also known as nuclear factor (erythroid‐derived 2)‐like 2 (NFE2L2), suppresses the transcription of C/EBPβ in SH‐SY5Y cells when treated with MPP(+). To activate Nrf2, sulforaphane, an Nrf2 activator, was administered. Additionally, C/EBPβ was silenced using C/EBPβ‐DNA/RNA heteroduplex oligonucleotide (HDO). Both approaches successfully reduced abnormal α‐Syn expression in primary neurons treated with MPP(+). Furthermore, sustained activation of Nrf2 via its activator or inhibition of C/EBPβ using C/EBPβ‐HDO resulted in a reduction of aberrant α‐Syn expression, thus leading to an improvement in the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) in mouse models induced by 1‐methyl‐4‐phenyl‐1,2,5,6‐tetrahydropyridine (MPTP) and those treated with preformed fibrils (PFFs). The data presented in this study illustrate that the activation of Nrf2 may provide a potential therapeutic strategy for PD by inhibiting the abnormal C/EBPβ/α‐Syn signaling pathway.