Roig and colleagues propose that DDR1 (discoidin domain receptor 1) is a new susceptibility gene for schizophrenia. It's of interest that it has been shown to bind SHP-2. (Wang et al., 2006). In view of the fact that Roig describes DDR1 as a myelin gene, and PZR (protein zero related) is a proposed substrate of SHP-2, might we suspect disruption of SHP-2 signaling in schizophrenia (Zhao et al., 1998)?

Activating mutations of SHP-2 are found in Noonan syndrome, in which both autism and schizophrenia have been reported. De Hert et al. found high levels of Helicobacter pylori in institutionalized schizophrenic patients (De Hert et al., 1997), and it would seem relevant that SHP-2 is activated by complex formation with Helicobacter pylori CagA. Might bacterial eradication result in the alleviation of symptoms of schizophrenia? Is it likely that periods of extreme stress predispose to gastric ulceration with a subsequent H. pylori infection (Hatakeyama, 2006)?

Activating mutations of SHP-2 promote neurogenesis and inhibit astrogenesis (Gauthier et al., 2007). Perhaps this is further evidence of increased SHP-2 activity as fewer astrocytes are reported in the frontal cortex in schizophrenia (Doyle and Deakin, 2002). Worth noting is that H2O2 inactivates SHP-2. In view of the study by Li and colleagues finding that olanzapine increases SOD1 concentrations (Li et al., 1999), which would result in increased H2O2, I wonder whether inactivation of SHP-2 provides part of the therapeutic benefit.

References:

Wang CZ, Su HW, Hsu YC, Shen MR, Tang MJ. A discoidin domain receptor 1/SHP-2 signaling complex inhibits alpha2beta1-integrin-mediated signal transducers and activators of transcription 1/3 activation and cell migration. Mol Biol Cell. 2006 Jun;17(6):2839-52. Epub 2006 Apr 12. Abstract

Zhao ZJ, Zhao R. Purification and cloning of PZR, a binding protein and putative physiological substrate of tyrosine phosphatase SHP-2. J Biol Chem. 1998 Nov 6;273(45):29367-72. Abstract

De Hert M, Hautekeete M, De Wilde D, Peuskens J. High prevalence of Helicobacter pylori in institutionalized schizophrenic patients. Schizophr Res. 1997 Aug 29;26(2-3):243-4. Abstract

Hatakeyama M. Helicobacter pylori CagA--a bacterial intruder conspiring gastric carcinogenesis. Int J Cancer. 2006 Sep 15;119(6):1217-23. Abstract

Gauthier AS, Furstoss O, Araki T, Chan R, Neel BG, Kaplan DR, Miller FD. Control of CNS cell-fate decisions by SHP-2 and its dysregulation in Noonan syndrome. Neuron. 2007 Apr 19;54(2):245-62. Abstract

Doyle C, Deakin JFW. Fewer astrocytes in frontal cortex in schizophrenia, depression and bipolar disorder. Schizophr Res 2002;53:106.

Li XM, Chlan-Fourney J, Juorio AV, Bennett VL, Shrikhande S, Keegan DL, Qi J, Boulton AA. Differential effects of olanzapine on the gene expression of superoxide dismutase and the low affinity nerve growth factor receptor. J Neurosci Res. 1999 Apr 1;56(1):72-5. Abstract

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