Genetic Control of Lithium Sensitivity and Regulation of Inositol Biosynthetic Genes

King, Jason, Keim, Melanie, Teo, Regina, Weening, Karin E., Kapur, Mridu, McQuillan, Karina, Ryves, Jonathan, Rogers, Ben, Dalton, Emma, Williams, Robin S. B. and Harwood, Adrian J.

(2010)

King, Jason, Keim, Melanie, Teo, Regina, Weening, Karin E., Kapur, Mridu, McQuillan, Karina, Ryves, Jonathan, Rogers, Ben, Dalton, Emma, Williams, Robin S. B. and Harwood, Adrian J. (2010) Genetic Control of Lithium Sensitivity and Regulation of Inositol Biosynthetic Genes. PLoS One, 5 (6).

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Abstract

Lithium (Li+) is a common treatment for bipolar mood disorder, a major psychiatric illness with a lifetime prevalence of more than 1%. Risk of bipolar disorder is heavily influenced by genetic predisposition, but is a complex genetic trait and, to date, genetic studies have provided little insight into its molecular origins. An alternative approach is to investigate the genetics of Li+ sensitivity. Using the social amoeba Dictyostelium, we previously identified prolyl oligopeptidase (PO) as a modulator of Li+ sensitivity. In a link to the clinic, PO enzyme activity is altered in bipolar disorder patients. Further studies demonstrated that PO is a negative regulator of inositol(1,4,5) trisphosphate (IP3) synthesis, a Li+ sensitive intracellular signal. However, it was unclear how PO could influence either Li+ sensitivity or risk of bipolar disorder. Here we show that in both Dictyostelium and cultured human cells PO acts via Multiple Inositol Polyphosphate Phosphatase (Mipp1) to control gene expression. This reveals a novel, gene regulatory network that modulates inositol metabolism and Li+ sensitivity. Among its targets is the inositol monophosphatase gene IMPA2, which has also been associated with risk of bipolar disorder in some family studies, and our observations offer a cellular signalling pathway in which PO activity and IMPA2 gene expression converge.

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This is a Submitted version
This version's date is: 17/6/2010
This item is not peer reviewed

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https://repository.royalholloway.ac.uk/items/f3d441f9-de40-d036-f9cd-5d573b26e4ea/6/

Item TypeJournal Article
TitleGenetic Control of Lithium Sensitivity and Regulation of Inositol Biosynthetic Genes
AuthorsKing, Jason
Keim, Melanie
Teo, Regina
Weening, Karin E.
Kapur, Mridu
McQuillan, Karina
Ryves, Jonathan
Rogers, Ben
Dalton, Emma
Williams, Robin S. B.
Harwood, Adrian J.
Uncontrolled KeywordsPERFORMANCE LIQUID-CHROMATOGRAPHY, MANIC-DEPRESSIVE PATIENTS, DIPEPTIDYL PEPTIDASE-IV, BIPOLAR DISORDER, DICTYOSTELIUM-DISCOIDEUM, PROLYL ENDOPEPTIDASE, ANTIPSYCHOTIC-DRUGS, MONOPHOSPHATASE, POLYPHOSPHATES, CELLS
DepartmentsFaculty of Science\Biological Science

Identifiers

doihttp://dx.doi.org/10.1371/journal.pone.0011151

Deposited by Research Information System (atira) on 22-Jul-2014 in Royal Holloway Research Online.Last modified on 22-Jul-2014


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