News Brief—Picking PIK3CD for Schizophrenia Treatment
30 July 2012. A new study published June 11 in Proceedings of the National Academy of Sciences plunges into the depths of neuregulin 1 (NRG1) signaling, and emerges with PIK3CD as a potential therapeutic target for schizophrenia. Amanda Law and colleagues at the National Institute for Mental Health in Bethesda, Maryland, probed the downstream workings of NRG1 and its receptor, ErbB4, which are involved in many cellular processes, including neural development and synaptic plasticity, and which have both been implicated in schizophrenia with genetic studies. As previously presented in 2011 at a New York Academy of Sciences meeting on Advancing Drug Discovery in Schizophrenia (see SRF related conference story), the team found signs of aberrant NRG1-ErbB4 signaling in schizophrenia, and reported that pharmacologically inhibiting a downstream protein encoded by PIK3CD blocks schizophrenia-related behaviors in rodents.
Drawing from human lymphoblastoid cell lines (LCLs) derived from patients with schizophrenia and controls, the researchers found an overabundance of an ErbB4 isoform, called CYT-1, in schizophrenia, and this isoform can bind to and activate phosphoinositide 3-kinase (PI3K). PIK3CD, which encodes a catalytic subunit of PI3K, was also elevated by 40 percent in schizophrenia compared to controls. Blocking PIK3CD might rectify this, and just such an inhibitor prevented amphetamine-induced locomotion in mice, and prepulse inhibition deficits in a rat model. Two family-based genetic studies also turned up single nucleotide polymorphisms in PIK3CD associated with schizophrenia. These and other data build a case for PIK3CDís involvement in schizophrenia, which the authors suggest may offer a way to fine-tune NRG1-ErbB4 signaling without messing with the myriad other processes governed by the pathway.—Michele Solis.
Law AJ, Wang Y, Sei Y, O'Donnell P, Piantadosi P, Papaleo F, Straub RE, Huang W, Thomas CJ, Vakkalanka R, Besterman AD, Lipska BK, Hyde TM, Harrison PJ, Kleinman JE, Weinberger DR. Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy. Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):12165-70. Abstract
Comments on Related News
Related News: NYAS 2011—New Molecular Targets for SchizophreniaComment by: Jim Woodgett
Submitted 26 April 2011
Posted 27 April 2011
Several of the reports from the NYAS meeting describe the potential role of GSK-3β in DISC1 functions. This is one of two isoforms, and the other, GSK-3α, tends to get short shrift from researchers. This is problematic for several reasons. Firstly, the two isoforms, despite being derived from distinct genes, are essentially identical within their catalytic domains. Consequently, there are no small molecule inhibitors that that are isoform selective, and the two proteins are highly redundant (albeit not completely) in function. Secondly, in the case of DISC1, there are new data indicating a role for GSK-3α in DISC1 functions. Small molecule (isoform indiscriminate) inhibitors of GSK-3 restore behavioral deficits of DISC1 L100P animals, and this is also achieved by genetic inactivation of one allele of GSK-3α (Lipina et al., 2011). Examination of the brains of the DISC1 and DISC1/GSK-3α+/- animals revealed that dendritic spine density deficits observed in DISC1 L100P brains were restored upon deletion of one copy of GSK-3α (Lee et al., 2011).
From a therapeutic point of view, there appears to be no easy way to selectively inhibit only one isoform of GSK-3 (the only means is via RNA interference), so perhaps it is fortunate that both isoforms appear to play similar roles? Birds, on the other hand, appear to have selectively lost GSK-3α, though the consequences in terms of brain development and function are currently unclear (Alon et al., 2011).
Lipina TV, Kaidanovich-Beilin O, Patel S, Wang M, Clapcote SJ, Liu F, Woodgett JR, Roder JC. (2011). Genetic and pharmacological evidence for schizophrenia-related Disc1 interaction with GSK-3. Synapse 65(3):234-48. Abstract
Lee FH, Kaidanovich-Beilin O, Roder JC, Woodgett JR, Wong AH. (2011) Genetic inactivation of GSK3α rescues spine deficits in Disc1-L100P mutant mice. Schizophr Res. Abstract
Alon LT, Pietrokovski S, Barkan S, Avrahami L, Kaidanovich-Beilin O, Woodgett JR, Barnea A, Eldar-Finkelman H. (2011) Selective loss of glycogen synthase kinase-3α in birds reveals distinct roles for GSK-3 isozymes in tau phosphorylation. FEBS Lett. 585(8):1158-62. Abstract
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