Unraveling the function of Arabidopsis thaliana OS9 in the endoplasmic reticulum-associated degradation of glycoproteins

In the endoplasmic reticulum, immature polypeptides coincide with terminally misfolded proteins. Consequently, cells need a well-balanced quality control system, which decides about the fate of individual proteins and maintains protein homeostasis. Misfolded and unassembled proteins are sent for destruction via the endoplasmic reticulum-associated degradation (ERAD) machinery to prevent the accumulation of potentially toxic protein aggregates. Here, we report the identification of Arabidopsis thaliana OS9 as a component of the plant ERAD pathway. OS9 is an ER-resident glycoprotein containing a mannose-6-phosphate receptor homology domain, which is also found in yeast and mammalian lectins involved in ERAD. OS9 fused to the C-terminal domain of YOS9 can complement the ERAD defect of the corresponding yeast Δyos9 mutant. An A. thaliana OS9 loss-of-function line suppresses the severe growth phenotype of the bri1-5 and bri1-9 mutant plants, which harbour mutated forms of the brassinosteroid receptor BRI1. Co-immunoprecipitation studies demonstrated that OS9 associates with Arabidopsis SEL1L/HRD3, which is part of the plant ERAD complex and with the ERAD substrates BRI1-5 and BRI1-9, but only the binding to BRI1-5 occurs in a glycan-dependent way. OS9-deficiency results in activation of the unfolded protein response and reduces salt tolerance, highlighting the role of OS9 during ER stress. We propose that OS9 is a component of the plant ERAD machinery and may act specifically in the glycoprotein degradation pathway

Effects of zonisamide in the treatment of alcohol dependence

OBJECTIVE: Anticonvulsant drugs have been used in the treatment of alcohol dependence. The purpose of the present study was to evaluate tolerance and safety of zonisamide in a sample of patients presenting alcohol dependence. METHODS: Open-label zonisamide was examined in 22 outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition alcohol dependence. Zonisamide was started at a dose of 50 mg/d and titrated to a maximun dose of 300 mg/d. Subjects received a baseline evaluation including Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and the Severity of Alcohol Dependence Scale. Alcohol craving and alcohol consumption were assessed at weeks 2, 4, 6, 8, 10, and 12. The concentration of γ-glutamyltransferase was used as an indirect measure of alcohol consumption. RESULTS: Significant improvement was observed in visual analog scale for craving severity scores, weekly drink consumption, and γ-glutamyltransferase. Zonisamide was well tolerated, with only a dropout due to adverse events. CONCLUSIONS: Zonisamide is safe and well tolerated in this sample and associated with improvement in alcohol craving and alcohol consumption. A placebo-controlled study would be of interest