C/EBPβ/AEP is age-dependently activated in Parkinson's disease and mediates α-synuclein in the gut and brain

Parkinson's disease (PD) is the most common neurodegenerative motor disorder, and its pathologic hallmarks include extensive dopaminergic neuronal degeneration in the Substantia nigra associated with Lewy bodies, predominantly consisting of phosphorylated and truncated alpha-Synuclein (alpha-Syn). Asparagine endopeptidase (AEP) cleaves human alpha-Syn at N103 residue and promotes its aggregation, contributing to PD pathogenesis. However, how AEP mediates Lewy body pathologies during aging and elicits PD onset remains incompletely understood. Knockout of AEP or C/EBP beta from alpha-SNCA mice, and their chronic rotenone exposure models were used, and the mechanism of alpha-Syn from the gut that spread to the brain was observed. Here we report that C/EBP beta/AEP pathway, aggravated by oxidative stress, is age-dependently activated and cleaves alpha-Syn N103 and regulates Lewy body-like pathologies spreading from the gut into the brain in human alpha-SNCA transgenic mice. Deletion of C/EBP beta or AEP substantially diminished the oxidative stress, neuro-inflammation, and PD pathologies, attenuating motor dysfunctions in aged alpha-SNCA mice. Noticeably, PD pathologies initiate in the gut and progressively spread into the brain. Chronic gastric exposure to a low dose of rotenone initiates Lewy body-like pathologies in the gut that propagate into the brain in a C/EBP beta/AEP-dependent manner. Hence, our studies demonstrate that C/EBP beta/AEP pathway is critical for mediating Lewy body pathology progression in PD.