Disorders of the Nervous System The Transcription Repressor REST in Adult Neurons: Physiology, Pathology, and Diseases1,2,3

REST [RE1-silencing transcription factor (also called neuron-restrictive silencer factor)] is known to repress thousands of possible target genes, many of which are neuron specific. To date, REST repression has been investigated mostly in stem cells anddifferentiatingneurons.Current evidencedemonstrates its importance in adult neuronsaswell. Low levels ofREST, which are acquired during differentiation, govern the expression of specific neuronal phenotypes. REST-dependent genes encode important targets, including transcription factors, transmitter release proteins, voltage-dependent and receptor channels, and signaling proteins. Additional neuronal properties depend onmiRNAs expressed reciprocally to REST and on specific splicing factors. In adult neurons, REST levels are not always low. Increases occur during aging in healthy humans. Moreover, extensive evidence demonstrates that prolonged stimulationwith various agents induces REST increases, which are associated with the repression of neuron-specific genes with appropriate, intermediate REST binding affinity. Whether neuronal increases in REST are protective or detrimental remains a subject of debate. Examples of CA1 hippocampal neuron protection upon depolarization, and of neurodegeneration upon glutamate treatment and hypoxia have been reported.RESTparticipation in psychiatric andneurological diseases hasbeen shown, especially inAlzheimer’s disease and Huntington’s disease, aswell as epilepsy. Distinct, complex roles of the repressor in these different diseases have emerged. In conclusion, REST is certainly very important in a large number of conditions. We suggest that the conflicting result