Glut9-mediated Urate Uptake Is Responsible for Its Protective Effects on Dopaminergic Neurons in Parkinson’s Disease Models

Considerable evidence has shown that elevated plasma or cerebrospinal fluid (CSF) urate levels correlated with a reduced risk of Parkinson’s disease (PD). Based on its anti-oxidative properties, urate might serve as one of promising neuroprotective candidates for PD. However, how urate is transported through cell membranes to exert its effects inside the cells in PD is largely unknown. To elucidate this, we showed that increased intracellular urate exerted its neuroprotective effects against 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity in MES23.5 cells and elevated urate could antagonize 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic neuronal death in urate oxidase (UOx) knockout (KO) mice. Its transporter, glucose transporter type 9 (Glut9), was observed up-regulated, which was caused by the activation of p53. These protective effects could be abolished by Glut9 blocker and p53 inhibitor. These results suggested that Glut9 was a functional urate transporter, whose up-regulation by activation of p53 resulted in the increased intracellular urate levels in PD models. Our findings suggest that Glut9 could be modified to modulate urate levels in dopaminergic neurons and urate-elevating strategies without increasing systemic levels to avoid side effects might serve as a potential therapeutic target for PD

Investigation of Behavioral Dysfunctions Induced by Monoamine Depletions in a Mouse Model of Parkinson's Disease

Parkinson's disease (PD) is characterized not only by typical motor symptoms, but also by nonmotor symptoms in the early stages. In addition to the loss of dopaminergic (DAergic) neurons, progressive degenerations of noradrenergic (NA) and serotonergic (5-HT) neurons were also observed. However, the respective effects and interactions of these monoamine depletions on certain nonmotor symptoms are still largely unknown. In the present study, we performed selective depletions of NA, 5-HT and DA in mice by intraperitioneal injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), 4-chloro-L-phenylalanine (pCPA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), respectively. DSP-4 led to a 34% decrease in the number of NAergic neurons in the locus coeruleus, and MPTP led to a 30% decrease in the number of DAergic neurons in the substantia nigra. Although there was no obvious change in the number of 5-HTergic neurons in the dorsal raphe nucleus after pCPA treatment, the levels of 5-HT and its metabolite in the frontal cortex and hippocampus were reduced, respectively. Locomotor activity deficit was induced by DA depletion and a decrease in traveled distance was potentiated by additional NA depletion. Despair-associated depressive-like behavior could be observed in every group. Anxiety states emerged only from the combined depletion of two or three monoamines. However, combined depletion of the three monoamines dramatically induced anhedonia, and it could also aggravate the depressive-like and anxiety behavior. Furthermore, NA depletion significantly reduced spatial learning and memory ability, which was not enhanced by additional 5-HT or DA depletion. Our data highlighted the interactive role of NA, 5-HT and DA in the motor, emotional and cognitive deficits, providing new insight into the complex orchestration of impaired monoaminergic systems that related to the pathology of PD

Myeloid cell-specific ABCA1 deletion does not worsen insulin resistance in HF dietinduced or genetically obese mouse models

Obesity-associated low-grade chronic inflammation plays an important role in the development of insulin resistance. The membrane lipid transporter ATP-binding cassette transporter A1 (ABCA1) promotes formation of nascent HDL particles. ABCA1 also dampens macrophage inflammation by reducing cellular membrane cholesterol and lipid raft content. We tested the hypothesis that myeloid-specific ABCA1 deletion may exacerbate insulin resistance by increasing the obesity-associated chronic low-grade inflammation. Myeloid cell-specific ABCA1 knockout (MSKO) and wild-type (WT) mice developed obesity, insulin resistance, mild hypercholesterolemia, and hepatic steatosis to a similar extent with a 45% high-fat (HF) diet feeding or after crossing into the ob/ob background. Resident peritoneal macrophages and stromal vascular cells from obese MSKO mice accumulated significantly more cholesterol. Relative to chow, HF diet markedly induced macrophage infiltration and inflammatory cytokine expression to a similar extent in adipose tissue of WT and MSKO mice. Among proinflammatory cytokines examined, only IL-6 was highly upregulated in MSKO-ob/ob versus ob/ob mouse peritoneal macrophages, indicating a nonsignificant effect of myeloid ABCA1 deficiency on obesity-associated chronic inflammation. In conclusion, myeloid-specific ABCA1 deficiency does not exacerbate obesity-associated low-grade chronic inflammation and has minimal impact on the pathogenesis of insulin resistance in both HF diet-induced and genetically obese mouse models

Genetic variations in the serotonergic system contribute to amygdala volume in humans.

The amygdala plays a critical role in emotion processing and psychiatric disorders associated with emotion dysfunction. Accumulating evidence suggests that amygdala structure is modulated by serotonin-related genes. However, there is a gap between the small contributions of single loci (less than 1%) and the reported 63-65% heritability of amygdala structure. To understand the "missing heritability," we systematically explored the contribution of serotonin genes on amygdala structure at the gene set level. The present study of 417 healthy Chinese volunteers examined 129 representative polymorphisms in genes from multiple biological mechanisms in the regulation of serotonin neurotransmission. A system-level approach using multiple regression analyses identified that nine SNPs collectively accounted for approximately 8% of the variance in amygdala volume. Permutation analyses showed that the probability of obtaining these findings by chance was low (p = 0.043, permuted for 1000 times). Findings showed that serotonin genes contribute moderately to individual differences in amygdala volume in a healthy Chinese sample. These results indicate that the system-level approach can help us to understand the genetic basis of a complex trait such as amygdala structure

Genetic variations in the serotonergic system contribute to amygdala volume in humans

The amygdala plays a critical role in emotion processing and psychiatric disorders associated with emotion dysfunction. Accumulating evidence suggests that amygdala structure is modulated by serotonin-related genes. However, there is a gap between the small contributions of single loci (less than 1%) and the reported 63-65% heritability of amygdala structure. To understand the "missing heritability," we systematically explored the contribution of serotonin genes on amygdala structure at the gene set level. The present study of 417 healthy Chinese volunteers examined 129 representative polymorphisms in genes from multiple biological mechanisms in the regulation of serotonin neurotransmission. A system-level approach using multiple regression analyses identified that nine SNPs collectively accounted for approximately 8% of the variance in amygdala volume. Permutation analyses showed that the probability of obtaining these findings by chance was low (p = 0.043, permuted for 1000 times). Findings showed that serotonin genes contribute moderately to individual differences in amygdala volume in a healthy Chinese sample. These results indicate that the system-level approach can help us to understand the genetic basis of a complex trait such as amygdala structure

Deubiquitylase OTUD3 Mediates Endoplasmic Reticulum Stress through Regulating Fortilin Stability to Restrain Dopaminergic Neurons Apoptosis

OTU domain-containing protein 3 (OTUD3) knockout mice exhibited loss of nigral dopaminergic neurons and Parkinsonian symptoms. However, the underlying mechanisms are largely unknown. In this study, we observed that the inositol-requiring enzyme 1α (IRE1α)-induced endoplasmic reticulum (ER) stress was involved in this process. We found that the ER thickness and the expression of protein disulphide isomerase (PDI) were increased, and the apoptosis level was elevated in the dopaminergic neurons of OTUD3 knockout mice. These phenomena were ameliorated by ER stress inhibitor tauroursodeoxycholic acid (TUDCA) treatment. The ratio of p-IRE1α/IRE1α, and the expression of X-box binding protein 1-spliced (XBP1s) were remarkably increased after OTUD3 knockdown, which was inhibited by IRE1α inhibitor STF-083010 treatment. Moreover, OTUD3 regulated the ubiquitination level of Fortilin through binding with the OTU domain. OTUD3 knockdown resulted in a decrease in the interaction ability of IRE1α with Fortilin and finally enhanced the activity of IRE1α. Taken together, we revealed that OTUD3 knockout-induced injury of dopaminergic neurons might be caused by activating IRE1α signaling in ER stress. These findings demonstrated that OTUD3 played a critical role in dopaminergic neuron neurodegeneration, which provided new evidence for the multiple and tissue-dependent functions of OTUD3

Haplotype polymorphism in the alpha-2B-adrenergic receptor gene influences response inhibition in a large Chinese sample.

Response inhibition refers to the suppression of inappropriate or irrelevant responses. It has a central role in executive functions, and has been linked to a wide spectrum of prevalent neuropsychiatric disorders. Increasing evidence from neuropharmacological studies has suggested that gene variants in the norepinephrine neurotransmission system make specific contributions to response inhibition. This study genotyped five tag single-nucleotide polymorphisms covering the whole alpha-2B-adrenergic receptor (ADRA2B) gene and investigated their associations with response inhibition in a relatively large healthy Chinese sample (N=421). The results revealed significant genetic effects of the ADRA2B conserved haplotype polymorphisms on response inhibition as measured by stop-signal reaction time (SSRT) (F(2, 418)=5.938, p=0.003). Individuals with the AAGG/AAGG genotype (n=89; mean SSRT=170.2 ms) had significantly shorter SSRTs than did those with either the CCAC/AAGG genotype (n=216; mean SSRT=182.4 ms; uncorrected p=0.03; corrected p=0.09) or the CCAC/CCAC genotype (n=116; mean SSRT=195.8 ms; corrected p<0.002, Cohen's d=0.51). This finding provides the first evidence from association research in support of a critical role of the norepinephrine neurotransmission system in response inhibition. A better understanding of the genetic basis of response inhibition would allow us to develop more effective diagnosis, treatment, and prevention of deficient or underdeveloped response inhibition as well as its related prevalent neuropsychiatric disorders