Pedigree-based study to identify GOLGB1 as a risk gene for bipolar disorder.

Bipolar disorder (BD) is a complex psychiatric disorder with strong heritability. Identification of new BD risk genes will help determine the mechanism underlying disease pathogenesis. In the present study, we carried out whole genome sequencing for a Chinese BD family with three affected members and three unaffected members, and identified multiple candidate causal variations, including a frameshift mutation in the GOLGB1 gene. Since a GOLGB1 missense mutation was also found in another BD pedigree, we carried out functional studies by downregulating Golgb1 expression in the brain of neonatal mice. Golgb1 deficiency had no effect on anxiety, memory, and social behaviors in young adult mice. However, we found that young adult mice with Golgb1 deficiency exhibited elevated locomotor activity and decreased depressive behaviors in the tail suspension test and the sucrose preference test, but increased depressive behaviors in the forced swim test, resembling the dual character of BD patients with both mania and depression. Moreover, Golgb1 downregulation reduced PSD93 levels and Akt phosphorylation in the brain. Together, our results indicate that GOLGB1 is a strong BD risk gene candidate whose deficiency may result in BD phenotypes possibly through affecting PSD93 and PI3K/Akt signaling.

RPS23RG1 modulates tau phosphorylation and axon outgrowth through regulating p35 proteasomal degradation.

Tauopathies are a group of neurodegenerative diseases characterized by hyperphosphorylation of the microtubule-binding protein, tau, and typically feature axon impairment and synaptic dysfunction. Cyclin-dependent kinase5 (Cdk5) is a major tau kinase and its activity requires p35 or p25 regulatory subunits. P35 is subjected to rapid proteasomal degradation in its membrane-bound form and is cleaved by calpain under stress to a stable p25 form, leading to aberrant Cdk5 activation and tau hyperphosphorylation. The type Ib transmembrane protein RPS23RG1 has been implicated in Alzheimer's disease (AD). However, physiological and pathological roles for RPS23RG1 in AD and other tauopathies are largely unclear. Herein, we observed retarded axon outgrowth, elevated p35 and p25 protein levels, and increased tau phosphorylation at major Cdk5 phosphorylation sites in Rps23rg1 knockout (KO) mice. Both downregulation of p35 and the Cdk5 inhibitor roscovitine attenuated tau hyperphosphorylation and axon outgrowth impairment in Rps23rg1 KO neurons. Interestingly, interactions between the RPS23RG1 carboxyl-terminus and p35 amino-terminus promoted p35 membrane distribution and proteasomal degradation. Moreover, P301L tau transgenic (Tg) mice showed increased tau hyperphosphorylation with reduced RPS23RG1 levels and impaired axon outgrowth. Overexpression of RPS23RG1 markedly attenuated tau hyperphosphorylation and axon outgrowth defects in P301L tau Tg neurons. Our results demonstrate the involvement of RPS23RG1 in tauopathy disorders, and implicate a role for RPS23RG1 in inhibiting tau hyperphosphorylation through homeostatic p35 degradation and suppression of Cdk5 activation. Reduced RPS23RG1 levels in tauopathy trigger aberrant Cdk5-p35 activation, consequent tau hyperphosphorylation, and axon outgrowth impairment, suggesting that RPS23RG1 may be a potential therapeutic target in tauopathy disorders.

Plasma levels of Interleukin 18 but not amyloid-ß or Tau are elevated in female depressive patients.

BACKGROUND: Depression is associated with inflammation and Alzheimer's disease (AD). However, detailed molecular mechanisms linking mood, neuroinflammation and AD remain unclear. Although changes in peripheral inflammatory factors such as Interleukin 18 (IL18), and AD-associated amyloid-ß (Aß) peptides have been linked to depression, a solid relationship between these factors in depressive disorder has yet to be established. This study aims to further determine whether plasma IL18, Aß40, Aß42, and the AD-associated tangle component Tau, as well as IL18 single nucleotide polymorphisms (SNPs) may be biomarkers for depression. METHODS: We measured plasma IL18, Aß40, Aß42, and Tau in 64 depressive patients and 75 healthy controls, and characterized genotypes of three IL18 SNPs (rs187238, rs1946518 and rs1946519) in these subjects. Comparisons between depressive patients and controls were carried out in males, in females or in combination. Regression analyses were conducted to examine the correlation between these parameters. RESULTS: We found that none of the plasma levels of IL18, Aß40, Aß42, and Tau, the ratio of Aß42/Aß40, and the genotypes of IL18 SNPs were significantly different between combined depressive patients and combined healthy controls, or between male depressive patients and male controls. However, IL18 levels were less in females than in males in healthy people and were significantly increased in female depressive patients compared to female controls. Moreover, IL18 and standardized IL18 were correlated with standardized Aß42/Aß40 ratio and standardized Tau in depressive patients. CONCLUSIONS: Plasma IL18 may be a potential biomarker for depression in women.

RPS23RG1 Is Required for Synaptic Integrity and Rescues Alzheimer's Disease-Associated Cognitive Deficits.

BACKGROUND: Although synaptic impairment is a prerequisite to cognitive deficiencies in Alzheimer's disease (AD), mechanisms underlying the dysregulation of essential synaptic scaffolding components and their integrity remain elusive. RPS23RG1 is a newly identified protein implicated in AD. However, the physiological function of RPS23RG1 has yet to be determined. METHODS: We investigated the role of RPS23RG1 in maintaining synaptic structure and function in cell cultures and in Rps23rg1 knockout mice and determined whether targeting RPS23RG1-mediated pathways has therapeutic potential in APP/PS1 AD model mice. RESULTS: Deletion of the Rps23rg1 gene resulted in severe memory deficits and impairment of postsynaptic structure and function, with marked reductions in postsynaptic densities-93 and -95 (PSD-93 and PSD-95) levels. RPS23RG1 interacted with PSD-93/PSD-95 through its intracellular domain, consequently sequestering PSD-93/PSD-95 from murine double minute 2-mediated ubiquitination and degradation, thereby maintaining synaptic function. Restoration of PSD-93/PS-D95 levels reversed synaptic and memory deficits in Rps23rg1 knockout mice. We further observed attenuated RPS23RG1 expression in human AD, which positively correlated with PSD-93/PSD-95 levels. Importantly, an RPS23RG1-derived peptide comprising a unique PSD-93/PSD-95 interaction motif rescued synaptic and cognitive defects in Rps23rg1 knockout and AD mouse models. CONCLUSIONS: Our results reveal a role for RPS23RG1 in maintaining synaptic integrity and function and provide a new mechanism for synaptic dysfunction in AD pathogenesis. This demonstrates that RPS23RG1-mediated pathways show good therapeutic potential in AD intervention.

Clinicopathological characteristics, treatment, and survival outcomes of cystadenocarcinoma of the salivary gland: a population-based study.

BACKGROUND: The aim of this study was to investigate the clinicopathological characteristics, treatment, and survival of cystadenocarcinoma of the salivary gland. PATIENTS AND METHODS: Cases in the Surveillance, Epidemiology, and End Results database from 1991 to 2012 were identified. Factors significantly associated with survival were identified using Kaplan-Meier survival analysis and Cox proportional hazard regression. RESULTS: A total of 65 patients were identified; of these patients, 64 received surgical treatment, 25 underwent lymphadenectomy, and four (16.0%) patients had nodal metastasis and only one (2.1%) patient had poorly differentiated disease. The most common tumor location was the parotid gland (87.7%). The median follow-up was 55 months. None of the patients died of salivary gland malignant-tumor-related disease. The 5- and 10-year cause-specific survival rates were 97.0% and 81.4%, respectively. The 5- and 10-year overall survival rates were 84.6% and 60.7%, respectively. Surgical procedures, lymphadenectomy, and adjuvant radiotherapy did not affect survival. CONCLUSION: Salivary gland cystadenocarcinoma is extremely rare but has an excellent prognosis, and surgery is the mainstay of treatment.

[A clinical study of paclitaxel combined with FOLFOX4 regimen as neoadjuvant chemotherapy for advanced gastric cancer].

OBJECTIVE: To evaluate the clinical efficacy and the toxicity of neoadjuvant chemotherapy with paclitaxel and FOLFOX4 (5-fluorouracil/leucovorin combined and oxaliplatin) regimen for advanced gastric cancer. METHODS: Seventy-eight patients with cTNM stage III or IV (M0) gastric cancer were enrolled and 39 were randomized into the treatment arm (n=39, paclitaxel combined with FOLFOX4 regimen neoadjuvant chemotherapy every two weeks in each cycle) and control group (n=39). Clinical response was evaluated with RECIST criteria after 3 cycles. Patients in experimental group received surgery after 2-4 weeks and postoperative chemotherapy of 3 cycles of the original regimen. When disease progressed, postoperative chemotherapy regimen was changed into ECF regimen. The control group of 39 patients received surgery within 2 weeks and postoperative chemotherapy of 6 cycles of paclitaxel combined with FOLFOX4 regimen. RESULTS: The clinical response rate was 66.7% in the treatment arm. The R0 resection rate (59.0%) was significantly higher than that in the control group (P=0.025) and the number of lymph node metastasis in the treatment arm(3.23±2.80) was significantly lower than that in the control group (5.79±2.69, P=0.001). There were no significant differences in postoperative complication rate (5.1% vs. 2.6%) and the number of lymph node dissection (19.69±2.95 vs. 20.59±3.22) between the two groups (P>0.05). The median survival time and 2-year survival rate in the treatment arm [(27.10±2.32) months and 59.0%] was significantly higher than that in the control group[(18.20±1.30) months and 28.2%] (P=0.001, P=0.006). Cox regression multivariable analysis showed that tumor differentiation, R0 resection, lymph node metastasis were independent prognostic factors. Adverse reaction of chemotherapy, mainly hematological adverse reactions, and peripheral nerve toxicity, were tolerable. No significant differences were noted between the two groups in adverse reactions (P>0.05). CONCLUSIONS: The efficacy of paclitaxel combined with FOLFOX4 as neoadjuvant chemotherapy is high. Patients tolerance and compliance are satisfactory. It can improve in patients with advanced gastric cancer the R0 resection rate, reduce lymph node metastasis and improve survival.