PLA2G6 mutations cause motor dysfunction phenotypes of young-onset dystonia-parkinsonism type 14 and can be relieved by DHA treatment in animal models.

Parkinson's disease (PD), the most common neurodegenerative motor disorder, is currently incurable. Although many studies have provided insights on the substantial influence of genetic factors on the occurrence and development of PD, the molecular mechanism underlying the disease is largely unclear. Previous studies have shown that point mutations in the phospholipase A2 group VI gene (PLA2G6) correlate with young-onset dystonia-parkinsonism type 14 (PARK14). However, limited information is available regarding the pathogenic role of this gene and the mechanism underlying its function. To study the role of PLA2G6 mutations, we first used zebrafish larvae to screen six PLA2G6 mutations and revealed that injection of D331Y, T572I, and R741Q mutation constructs induced phenotypes such as motility defects and reduction in dopaminergic neurons. The motility defects could be alleviated by treatment with L-3, 4-dihydroxyphenylalanine (L-dopa), indicating that these mutations are pathological for PARK14 symptoms. Furthermore, the injection of D331Y and T572I mutation constructs reduced phospholipase activity of PLA2G6 and its lipid metabolites, which confirmed that these two mutations are loss-of-function mutations. Metabolomic analysis revealed that D331Y or T572I mutation led to higher phospholipid and lower docosahexaenoic acid (DHA) levels, indicating that reduced DHA levels are pathological for defective motor functions. Further, a dietary DHA supplement relieved the motility defects in PLA2G6D331Y/D331Y knock-in mice. This result revealed that the D331Y mutation caused defective PLA2G6 phospholipase activity and consequently reduced the DHA level, which is the pathogenic factor responsible for PARK14. The results of this study will facilitate the development of therapeutic strategies for PARK14.

Chronic activation of NPFFR2 stimulates the stress-related depressive behaviors through HPA axis modulation.

Neuropeptide FF (NPFF) is a morphine-modulating peptide that regulates the analgesic effect of opioids, and also controls food consumption and cardiovascular function through its interaction with two cognate receptors, NPFFR1 and NPFFR2. In the present study, we explore a novel modulatory role for NPFF-NPFFR2 in stress-related depressive behaviors. In a mouse model of chronic mild stress (CMS)-induced depression, the expression of NPFF significantly increased in the hypothalamus, hippocampus, medial prefrontal cortex (mPFC) and amygdala. In addition, transgenic (Tg) mice over-expressing NPFFR2 displayed clear depression and anxiety-like behaviors with hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis, reduced expression of glucocorticoid receptor (GR) and neurogenesis in the hippocampus. Furthermore, acute treatment of NPFFR2 agonists in wild-type (WT) mice enhanced the activity of the HPA axis, and chronic administration resulted in depressive and anxiety-like behaviors. Chronic stimulation of NPFFR2 also decreased the expression of hippocampal GR and led to persistent activation of the HPA axis. Strikingly, bilateral intra-paraventricular nucleus (PVN) injection of NPFFR2 shRNA predominately inhibits the depressive-like behavior in CMS-exposed mice. Antidepressants, fluoxetine and ketamine, effectively relieved the depressive behaviors of NPFFR2-Tg mice. We speculate that persistent NPFFR2 activation, in particular in the hypothalamus, up-regulates the HPA axis and results in long-lasting increases in circulating corticosterone (CORT), consequently damaging hippocampal function. This novel role of NPFFR2 in regulating the HPA axis and hippocampal function provides a new avenue for combating depression and anxiety-like disorder.