Loss of nucleobindin-2 causes nigrastriatal degeneration in mice by impacting circadian rhythm-related genes and gut microbiota

Abstract Nesfatin-1 is a brain-gut peptide encoded by the nucleobindin-2 (NUCB2) gene. We previously demonstrated that a reduced level of nesfatin-1 in the cerebrospinal fluid, induced by intracerebroventricular injection of a nesfatin-1 antibody, is associated with degeneration of the nigrostriatal dopaminergic system. In combination with evidence that nesfatin-1 mediated the rescue of toxicant induced dopaminergic (DAergic) neuron loss in the substantia nigra (SN), as well as reduced nesfatin-1 levels in the blood of patients with Parkinson’s disease (PD), we raise the hypothesis that nesfatin-1 may be essential for the survival of DAergic neurons in SN in mice. In the present study, we found that whole-body Nucb2 knockout via CRISPR/Cas9 technology in mice led to nigrostriatal dopaminergic system degeneration, as evidenced by a reduction in tyrosine hydrolyses-immunoreactivity neurons in the SN, decreased levels of dopamine and its metabolites in the striatum, and mitochondrial and nuclear impairment in the SN. The underlying mechanism may involve oxidative stress and neuroinflammation induced by down-regulation of circadian rhythm-related gene expression. Furthermore, Nucb2 deletion in mice leads to intestinal microecological imbalance, disorder of the bacterial community structure, metabolic homeostasis disruption, and decreased abundance of some sleep rhythm-related bacterial communities and metabolites. Our findings reported that nesfatin-1 plays a role in maintaining the normal function of the nigrostriatal dopaminergic system, which may provide new therapeutic targets for PD.