GENOMIC STUDIES IDENTIFY NEUROTROPHIC CASCDES IN BIPOLAR DISORDER

Rulun

Zhou, Patricia Damschroder-Williams, Peixiong Yuan, Guang Chen and Husseini K.

Mood stabilizing agents

require chronic administration for therapeutic efficacy, a temporal profile

which suggests alterations at the genomic level. A series of microarray studies

have been undertaken to identify genes regulated by structurally highly

dissimilar mood stabilizers. Complementary proteomic studies have also been

investigating altered protein expression patterns.  Several novel and hitherto

completely unexpected targets have been identified. Indeed, using a

“knowledge-based” analysis, many of the genes can be categorized as (1) those

exerting trophic effects and regulating cell survival; (2) those regulating

critical cytoskeletal proteins; (3) those regulating cellular signaling; (4)

those regulating metabolic events. and cell death. Among these are transcription

factors, an mRNA binding protein, Bcl2-associated athanogene (Bag-1, which

regulates the glucocorticoid receptor and MAP kinases), and several members of

the Rho signaling cascade. The identification of  Bag-1 (which has been

validated at the protein level) is particularly noteworthy, since this protein

is involved in 3 cellular pathways that may have extreme relevance for the

treatment of severe mood disorders: (i) potentiation of the antiapoptotic

effects of bcl-2; (ii) activation of ERK MAP kinases; (iii) inhibition of

glucocorticoid receptor function. Among the most intriguing targets is

Bcl2-associated athanogene (Bag-1). The identification of Bag-1 is particularly

noteworthy, since this protein is involved in 3 cellular pathways that may have

extreme relevance for the treatment of severe mood disorders: (i) potentiation

of the antiapoptotic effects of bcl-2; (ii) activation of ERK MAP kinases; (iii)

inhibition of glucocorticoid receptor function. Following validation using

real-time PCR, as well as protein expression analysis, functional studies were

undertaken. Human neuroblastoma SH-SY5Y cells were co-transfected with 2

recombinant plasmid constructs:  glucocorticoid response element (GRE) and

glucocorticoid receptor alpha (GRa)

and a series of investigations were carried out. We found: (a) lithium can

inhibit glucocorticoid activation caused dexamethasone; the time frame and the

effective drug concentrations show the same pattern as that induced

up-regulation of bag-1; (b) the inhibitory effects can be attenuated by human

bag-1 siRNA. Taken together, these results suggest that regulating the

glucocorticoid pathway through bag-1 may have considerable importance in the

treatment of mood disorders. Furthermore, these studies have demonstrated the

utility of identifying both gene cluster categories as well as individual genes

which may represent therapeutically relevant targets for the actions of mood

Overall,

these studies have demonstrated the utility of identifying both gene cluster

categories as well as individual genes which may represent therapeutically

relevant targets for the actions of mood stabilizing agents. An analysis of the

temporal and spatial pattern of gene expression alterations in the brain may

provide important clues about the circuits involved in mood stabilization, and

have the potential to lead to the development of novel therapeutics. The

concerted use of genomic and proteomic strategies to refine these complex

diseases into mechanism-based subcategories may ultimately allow for the

matching of particular target-based therapies to particular markers in subgroups