Inhibition of abnormal C/EBP/-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 alpha-Synuclein (alpha-Syn), which has aggregated. A recent report proposes that CCAAT/enhancer-binding proteins beta (C/EBP beta) may act as an age-dependent transcription factor for alpha-Syn, thereby initiating PD pathologies by regulating its transcription. Potential therapeutic approaches to address PD could involve targeting the regulation of alpha-Syn by C/EBP beta. This study has revealed that Nrf2, also known as nuclear factor (erythroid-derived 2)-like 2 (NFE2L2), suppresses the transcription of C/EBP beta in SH-SY5Y cells when treated with MPP+. To activate Nrf2, sulforaphane, an Nrf2 activator, was administered. Additionally, C/EBP beta was silenced using C/EBP beta-DNA/RNA heteroduplex oligonucleotide (HDO). Both approaches successfully reduced abnormal alpha-Syn expression in primary neurons treated with MPP+. Furthermore, sustained activation of Nrf2 via its activator or inhibition of C/EBP beta using C/EBP beta-HDO resulted in a reduction of aberrant alpha-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/EBP beta/alpha-Syn signaling pathway.