Multiple Roles for Neuregulins and Their v-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog Receptors in Neurodegenerative Disease Pathogenesis and Therapy.

The role that neurotrophins, such as nerve growth factor, play in the pathogenesis of neurodegenerative diseases has long been appreciated. However, the neuregulin (NRG) family of growth factors and/or their v-erb-B2 avian erythroblastic leukemia viral oncogene homolog (ERBB) receptors have also been implicated in the pathogenesis of conditions, such as Alzheimer disease (AD), frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). In this review, we consider the structural variability of NRG isoforms generated by alternative RNA splicing, the use of multiple promoters and proteolysis, and the impact of this structural variability on neuronal and glial physiology during development and adulthood. We discuss the NRG receptors ERBB2, ERBB3, and ERBB4, how activation of each of these receptors further diversifies NRG actions in the central nervous system, and how dementia-related proteins, such as γ-secretase modulate the action of NRGs and their ERBB receptors. We then turn to the abnormalities in NRG and ERBB expression and function evident in human AD and mouse AD models, how these abnormalities affect brain function, and attempts to use NRGs to treat AD. Finally, we discuss the effects of NRG on the survival and function of neurons relevant to FTLD and ALS, alterations in NRG/ERBB signaling identified in these conditions, and the recent discovery of multiple human pedigrees in which autosomal dominant FTLD/ALS potentially results from point mutations in ERBB4.