Genetic mutations in the gene encoding transport protein particle complex 9 (trappc9), a subunit of TRAPP that acts as a guanine nucleotide exchange factor for rab proteins, cause intellectual disability with brain structural malformations by elusive mechanisms. Here, we report that trappc9-deficient mice exhibit a broad range of behavioral deficits and postnatal delay in growth of the brain. Contrary to volume decline of various brain structures, the striatum of trappc9 null mice was enlarged. An imbalance existed between dopamine D1 and D2 receptor containing neurons in the brain of trappc9-deficient mice; pharmacological manipulation of dopamine receptors improved performances of trappc9 null mice to levels of wild-type mice on cognitive tasks. Loss of trappc9 compromised the activation of rab11 in the brain and resulted in retardation of endocytic receptor recycling in neurons. Our study elicits a pathogenic mechanism and a potential treatment for trappc9-linked disorders including intellectual disability.
BackgroundAlthough the link between gut microbiota and depression has been suggested, changes of gut microbiota vary largely among individuals with depression.AimsExplore the heterogeneity of microbiota–gut–brain axis and new pathogenic characteristics in murine models of depression.MethodsAdolescent female mice were randomly divided into control (CON) group (n=10), chronic unexpected mild stress (CUMS) group (n=15) and dexamethasone (DEX) group (n=15). Mice in the DEX group were gavaged twice a day with 0.2 mg/kg of DEX for 5 weeks, whereas CON mice were given the same amount of solvent. Mice in the CUMS group were exposed to stressors. After behavioural evaluations, all mice were sacrificed for harvesting tissues and blood samples. Enzyme-linked immunosorbent assay (ELISA) was conducted for measuring levels of corticosterone (CORT) and interleukin-1β (IL-1β) in sera, whereas levels of protein expression in colon and hippocampal tissues were examined by western blot. Faecal microbial communities were analysed by sequencing 16S rDNAs.ResultsMice in CUMS and DEX groups exhibited severe depression-like behaviours. Compared with CON mice, CUMS-exposed mice showed a significant increase in both α and β diversity. Prevotellaceae and Desulfovibrio were enriched, whereas Bacilli were decreased in the faeces of mice in the CUMS group. DEX-treated mice had a decrease in the abundance of Clostridium XVIII. Levels of occludin in colon tissue of DEX-treated mice were reduced. Relative to mice in the CON and CUMS groups, DEX-treated mice contained higher serum levels of CORT and IL-1β. Compared with CON mice, mice in the DEX and CUMS groups had higher levels of IL-1β in sera and lower levels of glial fibrillary acidic protein (GFAP), Nestin, Synapsin-1 and P2Y12 receptor in the hippocampus.ConclusionsChanges of gut microbiota diversity, intestinal integrity and neuroinflammation in the brain contribute to CUMS-induced depression, whereas pathobionts and excessive immunosuppression with damaged neuronal synapses is a basis of the DEX-induced depression.
Genetic mutations of trappc9 cause intellectual disability with the atrophy of brain structures and variable obesity by poorly understood mechanisms. Trappc9-deficient mice develop phenotypes resembling pathological changes in humans and appear overweight shortly after weaning, and thus are useful for studying the pathogenesis of obesity. Here, we investigated the effects of trappc9 deficiency on the proliferation and differentiation capacity of adipose-derived stem cells (ASCs). We isolated ASCs from mice before overweight was developed and found that trappc9-null ASCs exhibited signs of premature senescence and cell death. While the lineage commitment was retained, trappc9-null ASCs preferred adipogenic differentiation. We observed a profound accumulation of lipid droplets in adipogenic cells derived from trappc9-deficient ASCs and marked differences in the distribution patterns and levels of calcium deposited in osteoblasts obtained from trappc9-null ASCs. Biochemical studies revealed that trappc9 deficiency resulted in an upregulated expression of rab1, rab11, and rab18, and agitated autophagy in ASCs. Moreover, we found that the content of neural stem cells in both the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus vastly declined in trappc9-null mice. Collectively, our results suggest that obesity, as well as brain structure hypoplasia induced by the deficiency of trappc9, involves an impairment in the plasticity of stem cells.
Mutant huntingtin, which causes Huntington’s disease (HD), is ubiquitously expressed but induces preferential loss of striatal neurons by unclear mechanisms. Rab11 dysfunction mediates homeostatic disturbance of HD neurons. Here, we report that Rab11 dysfunction also underscores the striatal vulnerability in HD. We profiled the proteome of Rab11-positive endosomes of HD-vulnerable striatal cells to look for protein(s) linking Rab11 dysfunction to striatal vulnerability in HD and found XK, which triggers the selective death of striatal neurons in McLeod syndrome. XK was trafficked together with Rab11 and was diminished on the surface of immortalized HD striatal cells and striatal neurons in HD mouse brains. We found that XK participated in transporting manganese, an essential trace metal depleted in HD brains. Introducing dominantly active Rab11 into HD striatal cells improved XK dynamics and increased manganese accumulation in an XK-dependent manner. Our study suggests that impaired Rab11-based recycling of XK onto cell surfaces for importing manganese is a driver of striatal dysfunction in Huntington’s disease.
Iguratimod (IGU, also known as T-614), a novel disease modifying antirheumatic drug intended to cure patients with rheumatoid arthritis (RA). The purpose of this study is to evaluate the effect of IGU on the pharmacokinetics of CYP2C9 probe drug diclofenac and its metabolite 4′-hydroxy diclofenac in vivo and in vitro. In in vivo experiments, 24 rats were randomly assigned to three groups consisting of the control group (Normal saline), low dose IGU group (10 mg/kg) and high dose IGU group (30 mg/ kg). Blood samples were collected from orbital sinuses vein before 1 hour and serial times of giving diclofenac (15 mg/kg) to all the rats. Plasma concentration of diclofenac and its metabolite 4´-hydroxy diclofenac were assayed by high performance liquid chromatography. Pharmacokinetic parameters were assessed by Winnonlin 6.4 pharmacokinetic software. Moreover, in vitro studies were performed in recombinant human CYP2C9 yeast cell system. IGU at low dose showed no significant differences in the pharmacokinetic parameters of diclofenac and 4-hydroxy diclofenac in vivo when compared with control group (p>0.005). However, at the high dose of IGU, the pharmacokinetic parameters of 4´-hydroxy metabolite of diclofenac increase in half-life (T 1/2 ) and mean area under the curve (AUC 0→24 ), while a decrease in mean clearance (CL, mL/h/kg) and volume of distribution Vz (mL/kg). In addition, in in vitro study, high doses of IGU reduces the metabolism rate of diclofenac. IGU at high dose significantly increase the pharmacokinetics parameters of 4´-hydroxy diclofenac in rats. Additionally, it also showed the potent inhibitory effect on diclofenac metabolism in recombinant human CYP2C9 yeast cells.
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