Activating transcription factor 2 (ATF2) is a member of the activator protein-1 family of transcription factors, which includes c-Jun and c-Fos. ATF2 is highly expressed in the mammalian brain although little is known about its function in nerve cells. Knockout mouse studies show that this transcription factor plays a role in neuronal migration during development but over-expression of ATF2 in neuronal-like cell culture promotes nerve cell death. Using immunohistochemical techniques we demonstrate ATF2 expression in the normal human brain is neuronal, is found throughout the cerebral cortex and is particularly high in the granule cells of the hippocampus, in the brain stem, in the pigmented cells of the substantia nigra and locus coeruleus, and in the granule and molecular cell layers of the cerebellum. In contrast to normal cases, ATF2 expression is down-regulated in the hippocampus, substantia nigra pars compacta and caudate nucleus of the neurological diseases Alzheimer's, Parkinson's and Huntington's, respectively. Paradoxically, an increase in ATF2 expression was found in the subependymal layer of Huntington's disease cases, compared with normal brains; a region reported to contain increased numbers of proliferating progenitor cells in Huntington's disease. We propose ATF2 plays a role in neuronal viability in the normal brain, which is compromised in susceptible regions of neurological diseases leading to its down-regulation. In contrast, the increased expression of ATF2 in the subependymal layer of Huntington's disease suggests a role for ATF2 in some aspect of neurogenesis in the diseased brain.