Chronic
constipation is one of the most prominent
prodromal symptoms in
Parkinson's disease (PD), and Lewy bodies, enriched with aggregated α-
Synuclein (α-Syn), propagation from the gut into the brain has been proposed to play a key role in PD etiopathogenesis.
BDNF (
Brain-derived neurotrophic factor) and
Netrin-1 promote both neuronal survival and regulate the gut functions. We hypothesize that C/EBPβ represses
BDNF and
Netrin-1 in peripheral nervous system and central nervous system, contributing to GI tract and brain malfunctions in PD. To test the hypothesis, we performed the studies in both human PD gut tissues and
BDNF or
Netrin-1 gut conditional KO mice models. Lewy bodies with α-Syn aggregation and neuro-
inflammation were measured in the colon and brain samples from PD patients and healthy controls and
rotenone or vehicle-treated WT and CEBPβ (+/-) mice. We show that both
BDNF and
Netrin-1 are strongly decreased in the brain and the gut of PD patients, and conditional KO of these trophic factors in the gut elicits dopaminergic neuronal loss,
constipation and motor dysfunctions. Interestingly, the
inflammation and oxidative stress-induced
transcription factor C/EBPβ acts as a robust repressor for both
BDNF and
Netrin-1 and suppresses the expression of trophic factors, and its levels inversely correlate with
BDNF and
Netrin-1 in PD patients. Our findings support that gut
inflammation induces C/EBPβ activation that leads to both
BDNF and
Netrin-1 reduction and triggers PD non-motor and motor symptoms. Possibly, C/EBPβ-mediated biological events might be early diagnostic
biomarkers for PD.