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Review
. 2009 Jan;34(1):18-54.
doi: 10.1038/npp.2008.172. Epub 2008 Oct 15.

Target identification for CNS diseases by transcriptional profiling

C Anthony Altar  1 , Marquis P Vawter, Stephen D Ginsberg
Affiliations
Review

Target identification for CNS diseases by transcriptional profiling

C Anthony Altar et al. Neuropsychopharmacology. 2009 Jan.

Abstract

Gene expression changes in neuropsychiatric and neurodegenerative disorders, and gene responses to therapeutic drugs, provide new ways to identify central nervous system (CNS) targets for drug discovery. This review summarizes gene and pathway targets replicated in expression profiling of human postmortem brain, animal models, and cell culture studies. Analysis of isolated human neurons implicates targets for Alzheimer's disease and the cognitive decline associated with normal aging and mild cognitive impairment. In addition to tau, amyloid-beta precursor protein, and amyloid-beta peptides (Abeta), these targets include all three high-affinity neurotrophin receptors and the fibroblast growth factor (FGF) system, synapse markers, glutamate receptors (GluRs) and transporters, and dopamine (DA) receptors, particularly the D2 subtype. Gene-based candidates for Parkinson's disease (PD) include the ubiquitin-proteosome system, scavengers of reactive oxygen species, brain-derived neurotrophic factor (BDNF), its receptor, TrkB, and downstream target early growth response 1, Nurr-1, and signaling through protein kinase C and RAS pathways. Increasing variability and decreases in brain mRNA production from middle age to old age suggest that cognitive impairments during normal aging may be addressed by drugs that restore antioxidant, DNA repair, and synaptic functions including those of DA to levels of younger adults. Studies in schizophrenia identify robust decreases in genes for GABA function, including glutamic acid decarboxylase, HINT1, glutamate transport and GluRs, BDNF and TrkB, numerous 14-3-3 protein family members, and decreases in genes for CNS synaptic and metabolic functions, particularly glycolysis and ATP generation. Many of these metabolic genes are increased by insulin and muscarinic agonism, both of which are therapeutic in psychosis. Differential genomic signals are relatively sparse in bipolar disorder, but include deficiencies in the expression of 14-3-3 protein members, implicating these chaperone proteins and the neurotransmitter pathways they support as possible drug targets. Brains from persons with major depressive disorder reveal decreased expression for genes in glutamate transport and metabolism, neurotrophic signaling (eg, FGF, BDNF and VGF), and MAP kinase pathways. Increases in these pathways in the brains of animals exposed to electroconvulsive shock and antidepressant treatments identify neurotrophic and angiogenic growth factors and second messenger stimulation as therapeutic approaches for the treatment of depression.

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Figures

Figure 1
Figure 1
Gene-based drug discovery strategies based on disease-specific (left) and drug-induced (right) mRNA expression changes. Information from these data, the literature, and other factors described in the text are used to select a smaller set of genes that change reciprocally between human brain and drug-exposed tissue, and are used for gene-based compound screening or identification of specific targets.
Figure 2
Figure 2
Single-cell microaspiration and classes of transcripts on a custom-designed cDNA array. (a) A p75NTR-immunoreactive neuron in the nucleus basalis of an AD patient is shown. (b) Same section as (a) following single-cell microaspiration. (c) Classes of transcripts analyzed in single-cell preparations using a custom-designed cDNA array platform (n = 576 genes). Scale bar: 50 µm. Adapted from Ginsberg et al (2000) with permission.
Figure 3
Figure 3
LCM is used to collect dentate neurons from the human hippocampus (shown in lower power, top left) (a). The top right micrograph (b) is an enlargement that shows the blue-stained dentate neurons before LCM. In the lower right (d), the LCM captured neurons are isolated and gene expression is measured in cDNA produced from their amplified RNA. The ‘hole’ after LCM can be seen in the lower left micrograph (c).
Figure 4
Figure 4
Splicing variations in glutathione S-transferase M1 (GSTM1) between eight individuals identified by exon array. The X axis points represent six exons within this gene. The Y axis represents the relative abundance of their expression. Note that the 3′ (left) and 5′ (right) ends of the gene show similar expression levels among people, but the fourth and fifth exons of the GSTM1 gene vary in the expression of this transcript.
Figure 5
Figure 5
Gene miniarray for antipsychotic drug discovery. Human neuroblastoma cells were cultured for 24 h in wells of a 96-well plate, in the presence of vehicle or 20 nM human insulin. RNA from the lysed cells was added to the MPHTSSM plate, which contains the illustrated 4 × 4 array of spotted cDNA for the genes. Typical increases by insulin vs the vehicle (control) were observed in quadruplicate by changes in fluorescence for each gene relative to two control genes, TAF10 and GTF3C1.
Figure 6
Figure 6
Expression profiling in neurofibrillary tangles (NFTs) bearing CA1 pyramidal neurons in postmortem AD brain. (a) Dopamine (DA) receptors D1–D5 are significantly decreased (*p<0.001; *p<0.05) in AD NFT-bearing CA1 neurons as evidenced by representative custom cDNA arrays. (b) Downregulation of several synaptic-related markers (*p <0.01; including synaptotagmin, SYP, synapsin I, α-synculein, and β-synuclein) is presented in a representative custom cDNA arrays and a histogram. In contrast, the relative expression of 4Rτ did not vary across the cohort, although the ratio between 3R/4Rτ is altered in AD. Adapted from Galvin and Ginsberg (2005) and Ginsberg et al (2000) with permission.
Figure 7
Figure 7
D1–D5 receptor expression levels in normal aging. The color-coded heatmap illustrates differential regulation of each receptor within individual CA1 pyramidal neurons and entorhinal stellate cells across a normal aged cohort. (a) Relative expression levels of the DA receptors, dopamine transporter (DAT), β-actin (ACTB), and 4-repeat τ (4Rτ) within individual CA1 pyramidal neurons microaspirated from postmortem human brains (aged of 19–92 years) (Hemby et al, 2003). Significant downregulations of DRD1–DRD5 were found (*p<0.001. No differential regulation of DAT, ACTB, and 4Rτ was observed, indicating a relative specificity of age-related transcript decline. (b) In contrast to the observations in CA1 pyramidal neurons, no differential regulation of DA receptors was observed within individual entorhinal cortex stellate cells. Adapted from Galvin and Ginsberg (2005) with permission.
Figure 8
Figure 8
Overlap in genes decreased (top) and increased (bottom) between two cohorts of schizophrenic cohorts and controls, n = 9 controls and 8 schizophrenics (cohort 1), and 15 controls and 14 schizophrenics (cohort 2). Over 95% of the genes that changed (p<0.05) in both cohorts changed in the same direction (Altar et al, 2005).
Figure 9
Figure 9
Reversal of schizophrenia gene signature (red bars) (Altar et al, 2005) by muscarinic agonists, 25 µM acetylcholine (yellow bars) and 25 µM oxotremorine (blue bars; Altar et al, 2008). A ‘+’ next to gene names signifies that it changed in response to insulin, and in a direction similar to the muscarinic agonists. Black border around bars indicates a significant change from vehicle control, p<0.05.
Figure 10
Figure 10
Glutamate–glutamine shuttle between glutamatergic nerve terminals and astroglia in the CNS. Increased expression of GLUL and SLC1A2 genes in schizophrenia and bipolar disorder (Shao and Vawter, 2008; Vawter et al, 2006a; Choudary et al, 2005; Beasley et al, 2006) and increased expression of GLS (Bruneau et al, 2005; Gluck et al, 2002) have been reported in schizophrenia, whereas decreased SLC1A2 and AGXT2L1 mRNA and GLUL mRNA and protein levels in major depressive disorder in the anterior cingulate were reported (Shao and Vawter, 2008; Vawter et al, 2006a; Choudary et al, 2005; Beasley et al, 2006). These molecules contribute to the transport, synthesis, and recycling of glutamate after synaptic release (Magistretti et al, 1999). Glutamate does not cross the blood–brain barrier and its presence in the CNS is from the glia-derived precursor, glutamine. SLC1A2 (solute carrier family 1 (glial high-affinity glutamate transporter, member 2)), AGXT2L1 (alanine-glyoxylate aminotransferase 2-like 1), GLUL (glutamate-ammonia ligase (glutamine synthetase)), SLC38A1 (solute carrier family 38, member 1), and GLS (glutaminase) are involved in this process and, as shown by arrows, are mostly increased in schizophrenia.
Figure 11
Figure 11
Fibroblast growth factor (FGF) signaling through diverse pathways. In total, 23 FGF family member ligands bind to four different FGF receptors (FGFR 1, 2, 3, and 4) and activate downstream signaling through FGFR homodimerization (shown by FGFR and FGFR). FGF signaling promotes the transcription of genes involved in proliferation, energy, growth, survival, angiogenesis, neurite extension, and growth cone motility. These signaling pathways can also be triggered by neural cell adhesion molecule (NCAM1) binding to an FGFR1 or FGFR2–NCAM heterodimer (Doherty and Walsh, 1996; Christensen et al, 2006). Peptide mimetics are being tested for their NCAM-like binding to FGFR1 or 2. Such agonism is anticipated to treat cognitive deficits, schizophrenia, and AD (Secher et al, 2006; Klementiev et al, 2007).
Figure 12
Figure 12
Cumulative number (X axis) and fold change (Y axis) of gene changes in the frontal cortex and hippocampus of rats treated with acute or chronic ECS. For all genes that changed (p <0.05) from sham seizure control rats, the ratio of the mean expression in the ECS group over the control group is cumulated over the magnitude of change. In each graph, decreases are plotted below the unity line and increases are plotted above the line. The X axes for all four graphs are aligned at ‘0 genes changed’ and plotted at the same scale so that the width of the graph represents the number of genes that were significantly increased or decreased by ECS (Altar et al, 2004).
Figure 13
Figure 13
Biochemical pathways implicated in the responses to ECS, based on statistically significant increases in gene expression (colored rectangle or oval labels) in the rodent hippocampus and/or frontal cortex following chronic ECS (Altar et al, 2005). GLUR1 and PGD synthase were decreased by ECS. Also reported by other groups in response to ECS, these genes included those within neurotrophic signaling pathways, including those for BDNF/MAP kinase, cAMP, and arachidonic acid signaling.
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