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.
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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