Neuregulin 1 (NRG1) is a protein that serves as a communicator between cells throughout the body. It plays a role in various biological processes, from the earliest stages of development to the maintenance of adult tissues. Understanding NRG1 offers insights into how cells interact and how these interactions can go awry in disease.
Understanding Neuregulin 1
NRG1 is a signaling protein, acting as a messenger between cells. It belongs to the neuregulin family, which includes NRG2, NRG3, and NRG4; NRG1 is the most extensively studied. NRG1 exerts its effects by binding to specific receptor proteins on target cells. These receptors are part of the ErbB family (ErbB1, ErbB2, ErbB3, and ErbB4).
When NRG1 binds to ErbB receptors, they form dimers. This pairing activates various intracellular signaling pathways. These pathways then trigger specific cellular responses, such as cell growth, movement, specialization, or even programmed cell death. The NRG1 gene produces many isoforms of the protein through alternative splicing. These isoforms have distinct structures and functions and are found in different tissues.
Essential Functions in Development and Beyond
NRG1 is involved in the formation and maintenance of several body systems. In the nervous system, it helps in the development of nerve cells, including Schwann cells, which produce myelin. Myelin is a fatty sheath that insulates nerve fibers, allowing electrical signals to travel quickly and efficiently. NRG1 encourages the growth and migration of these myelin-forming cells, and altered levels of a specific NRG1 isoform can affect myelination.
Beyond myelination, NRG1 also contributes to how nerve cells communicate at junctions called synapses. It influences synaptic plasticity, which is the ability of synapses to strengthen or weaken over time, a process important for learning and memory. In the cardiovascular system, NRG1 is involved in the formation of the heart, including the ventricular walls and heart valves. It also supports the health and function of heart muscle cells, helping them adapt to stress and maintain the heart’s pumping ability.
Neuregulin 1’s Role in Disease
Dysregulation of NRG1 signaling has been linked to several health conditions. In the brain, altered NRG1 levels or function are associated with neurological disorders like schizophrenia. Studies suggest that genetic variations in the NRG1 gene may increase the risk for schizophrenia. These genetic links are supported by NRG1’s influence on neurodevelopment, neurotransmitter receptor expression, and synaptic plasticity, all involved in schizophrenia.
NRG1 is also implicated in major depressive disorder and bipolar disorder, linked to white matter abnormalities in the brain, a common feature across these conditions. Abnormal NRG1 levels have been negatively associated with white matter integrity in various brain regions in patients with these disorders. In the heart, NRG1 signaling is involved in conditions such as heart failure. While NRG1 plays a protective role in the heart, its dysregulation can contribute to heart damage, as seen with certain cancer therapies that cause cardiotoxicity by blocking ErbB receptors. Furthermore, NRG1 gene fusions, where NRG1 combines with other genes, have been identified in certain cancers, including non-small cell lung cancer, pancreatic cancer, and breast cancer.
Targeting Neuregulin 1 for Treatment
Understanding NRG1’s roles in disease has opened avenues for potential therapies. In heart failure, recombinant human NRG1 (rhNRG1) has shown promise in animal models by improving heart function and reducing fibrosis. Clinical trials are exploring the use of recombinant NRG1 to enhance cardiac function in patients with systolic dysfunction and heart failure. These treatments aim to leverage NRG1’s ability to promote heart cell survival, growth, and repair.
For neurological disorders, research is exploring ways to modulate NRG1 signaling to improve cognitive outcomes, particularly in conditions like schizophrenia. This could involve gene therapies that aim to alter the expression of specific NRG1 molecules in brain circuits. In cancer, particularly in tumors with NRG1 fusions, therapies that target ErbB receptors are being investigated. These approaches aim to disrupt the uncontrolled cell growth driven by aberrant NRG1 signaling in cancer cells.