14-3-3γ haploinsufficiency leads to altered dopamine pathway and Parkinson’s disease-like motor incoordination in mice

Abstract

The 14-3-3 protein family with seven isoforms found in mammals is widely expressed in the brain and plays various roles in cellular processes. Several studies have reported that 14-3-3 gamma, one of the 14-3-3 protein isoforms, is associated with neurological and psychiatric disorders, but the role of 14-3-3 gamma in the pathophysiology of brain diseases is unclear. Although studies have been conducted on the relationship between 14-3-3 gamma protein and Parkinson's disease (PD), a common neurodegenerative disorder with severe motor symptoms such as bradykinesia and rigidity, a direct connection remains to be elucidated. We recently showed that adult heterozygous 14-3-3 gamma knockout mice are hyperactive and exhibit anxiety-like behavior. In this study, we further characterized the molecular and behavioral changes in aged 14-3-3 gamma heterozygous mice to investigate the role of 14-3-3 gamma in the brain. We observed decreased dopamine levels and altered dopamine metabolism in the brains of these mice, including changes in the phosphorylation of proteins implicated in PD pathology. Furthermore, we confirmed that they displayed PD symptom-like behavioral deficits, such as impaired motor coordination and decreased ability to the nest-building activity. These findings suggest an association between 14-3-3 gamma dysfunction and PD pathophysiology.