BACE1 Dependent Neuregulin Proteolysis

Neuregulin-1 (NRG1), which is also called acetylcholine receptor inducing activity (ARIA) or glial growth factor (GGF), signals as a ligand of ErbB receptors in a variety of important developmental processes but also later in life. NRG1 mediated signaling is crucial for cardiogenesis and the development of the breast. In the nervous system, NRG1 functions are essential for peripheral myelination, the establishment and maintenance of neuromuscular and sensorimotoric systems as well as for the plasticity of cortical neuronal circuits. There is strong evidence that deregulation of NRG1 is involved in breast cancer and schizophrenia. Many splice variants of NRG1 are expressed in the brain and all contain an EGF-like domain, which exerts the NRG1 function by limited proteolysis from its membrane bound precursor protein. In addition, most NRG1 isoforms contain a transmembrane domain, which is processed by γ-secretase after shedding. β-Secretase (β-site amyloid precursor protein cleaving enzyme 1; BACE1) has been identified based on its role as the rate limiting enzyme of amyloid-β-peptide (Aβ) production. Aβ is the major component of amyloid plaques in Alzheimer`s disease (AD). More recently it was shown that Neuregulin-1 activity is highly dependent on the cleavage by BACE1 during early postnatal development. In BACE1 KO mice a role for BACE1 dependent proteolysis of NRG1 in the process of peripheral myelination could be demonstrated. Here we summarize the current knowledge about the role of NRG1 proteolysis for ErbB receptor mediated signaling during development and in Alzheimer`s disease.