A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder
MOLECULAR PSYCHIATRY
Authors: Sellgren, C. M.; Kegel, M. E.; Bergen, S. E.; Ekman, C. J.; Olsson, S.; Larsson, M.; Vawter, M. P.; Backlund, L.; Sullivan, P. F.; Sklar, P.; Smoller, J. W.; Magnusson, P. K. E.; Hultman, C. M.; Walther-Jallow, L.; Svensson, C. I.; Lichtenstein, P.; Schalling, M.; Engberg, G.; Erhardt, S.; Landen, M.
Abstract
Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant-associated with reduced SNX7 expression-to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1 beta and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.
Overexpression of SNX7 reduces A beta production by enhancing lysosomal degradation of APP
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Authors: Xu, Shaohua; Zhang, Lu; Brodin, Lennart
Abstract
Abnormal production of amyloid-beta peptides (A beta) by proteolytic processing of amyloid precursor protein (APP) is thought to be central to the pathogenesis of Alzheimer's disease (AD). Although many efforts have been made to investigate mechanisms that regulate APP processing, many details remain incompletely understood. Sorting nexins (SNXs) are a family of proteins which are involved in many intracellular trafficking events. Several SNXs have been implicated in APP processing and A beta production. In this study, we extended the investigation to SNX7. We found that overexpression of SNX7 in HEK293T cells reduces the levels of secreted A beta and beta-cleaved N-terminal APP fragments (sAPP beta). Moreover, SNX7 overexpression caused a significant reduction of the steady-state levels of APP as well as of the cell surface APP levels. By using NH4CI and Bafilomycin A1 to inhibit the lysosomal degradative pathway, we found that the reduction of APP induced by SNX7 overexpression was prevented by such inhibition. No change in the cell surface distribution or steady-state levels of BACE1 was detected after overexpression of SNX7. Taken together, these results suggest that SNX7 regulates A beta production by directing APP for degradation. (C) 2017 Elsevier Inc. All rights reserved.
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