Emerging Role of DREAM in Healthy Brain and Neurological Diseases

Abstract

The downstream regulatory element antagonist modulator (DREAM) is a multifunctional Ca²⁺-sensitive protein exerting a dual mechanism of action to regulate several Ca²⁺-dependent processes. Upon sumoylation, DREAM enters in nucleus where it downregulates the expression of several genes provided with a consensus sequence named dream regulatory element (DRE). On the other hand, DREAM could also directly modulate the activity or the localization of several cytosolic and plasma membrane proteins. In this review, we summarize recent advances in the knowledge of DREAM dysregulation and DREAM-dependent epigenetic remodeling as a central mechanism in the progression of several diseases affecting central nervous system, including stroke, Alzheimer's and Huntington's diseases, amyotrophic lateral sclerosis, and neuropathic pain. Interestingly, DREAM seems to exert a common detrimental role in these diseases by inhibiting the transcription of several neuroprotective genes, including the sodium/calcium exchanger isoform 3 (NCX3), brain-derived neurotrophic factor (BDNF), pro-dynorphin, and c-fos. These findings lead to the concept that DREAM might represent a pharmacological target to ameliorate symptoms and reduce neurodegenerative processes in several pathological conditions affecting central nervous system.

Keywords: DREAM; KCNIP3; calsenilin; neurodegeneration.

Figure 1

Possible mechanisms of DREAM action. (1) High [Ca²⁺] levels inhibits the transcriptional activity of DREAM; (2) DREAM participates in the plasma membrane trafficking of the Kv4.2 potassium channel; (3) DREAM sumoylation allows entering into the nucleus to exert as transcription and/or epigenetic factor; (4) DREAM regulates the transcription of proteins involved in the maintenance of Ca²⁺ homeostasis; (5) DREAM regulates the activity of NMDA receptors by directly inhibiting the NR1 subunit; (6) DREAM participates in the regulation of presenilin 2 activity; (7) DREAM, upon low levels of [Ca²⁺], directly binds to CREB and prevents its phosphorylation and thus its transcriptional activity. Abbreviations: APP, amyloid precursor protein; NMDA-R, N-methyl-D-aspartate receptor; PS-2, presenilin-2; NCX3, Na⁺/Ca²⁺ exchanger 3; GFAP, Glial fibrillary acidic protein.

Figure 2

Transcriptional regulations of DREAM. (A) Upon low levels of [Ca²⁺]_n, DREAM forms a tetramer that binds to DRE sequences on the target genes and inhibits their transcription. Furthermore, DREAM directly binds to CREB preventing its PKA-dependent phosphorylation and, thus, its activating transcription. (B) Upon the rise in [Ca²⁺]_n levels, DREAM is inactivated, allowing for the detachment of this Ca²⁺-sensor protein from DRE sequences and CREB protein. Then, CREB can be phosphorylated and can bind the coactivator CBP, which, in turn, recruits the basal transcription activator factors (TAFs), TATA-binding protein (TBP) and transcription factor TFIIB. The resulting complex stabilizes RNA polymerase II, contributing to the assembly of the transcriptional initiation complex and, ultimately, relieves the transcriptional repression of target genes.

Figure 3

Epigenetic regulation of the gene encoding for Na⁺/Ca²⁺ exchanger isoform 3 (NCX3) following stroke. (1) Experimental stroke injury increases DREAM expression in peri-ischemic temporoparietal cortex region (2); under these conditions, DREAM recruits the epigenetic enzymes histone deacetylase isoform 4 and 5 (HDAC4 and HDAC5), forming a complex (3) that binds to the DRE sequence on ncx3 gene promoter (4); this complex deacetylates lysins of histones on ncx3 promoter and inhibits the expression of ncx3 gene (5); this process ultimately increases neuronal damage following stroke (6).