Atrophins' emerging roles in development and neurodegenerative disease.

The Atrophins are a widely expressed family of transcriptional co-regulators found in all metazoans. Atrophin1 was first identified as a neurodegenerative disease gene whereas Atrophin2 was identified based on homology. Phylogenetic studies indicate that the primordial Atrophin was an Atrophin2 type of gene and Atrophin2 has critical functions in normal mouse embryonic development whereas Atrophin1 is dispensable. Atrophins can interact with a wide range of proteins including membrane receptors, nuclear hormone receptors and other DNA binding transcription factors and can shuttle between the cytoplasm and the nucleus. In the nucleus, Atrophins can act as either co-repressors or co-activators and taken together this suggests that they are intermediaries in transcriptional responses to a diverse array of exogenous signals. Despite progress in understanding the normal role of Atrophins, the mechanism whereby mutations in Atrophin1 cause neurodegeneration has remained enigmatic, although most studies have focused on the idea that neurodegeneration is related to inappropriate transcriptional repression.