Abstract
Dopamine (DA) is a critical neurotransmitter which modulates motor functions, learning and motivation. Abnormal DA signaling is related to neuronal diseases such as schizophrenia (SZ) and Parkinson's disease (PD). The symptoms of SZ are classified as hyperDAergic positive symptoms and hypoDAergic negative symptoms. PD is a common progressive neurodegenerative disorder characterized by the loss and degradation of DAergic neurons. Current drugs poorly treat both diseases.
Ceramide kinase (CerK) is an enzyme which phosphorylates ceramide, a central metabolite of sphingolipids to produce ceramide-1-phosphate (C1P). CerK/C1P pathway is reported to be involved in extracellular homeostasis of some neurotransmitters in vitro, however, the involvement with SZ or PD remains unclear.
In this study, we created SZ and PD model in mice genetically deleted Cerk and compared their phenotypes with wild-type mice. We found that Cerk deficiency exacerbated the positive symptoms of SZ partly due to an increase in the extracellular DA levels. In contrast, negative symptoms of SZ and motor dysfunction of PD were partly improved by Cerk deficiency.
These results suggest that CerK may be a new therapeutic target for hypoDAergic diseases such as negative symptoms of SZ and PD by regulating extracellular DA levels.
