Differential distribution of neuregulin in human brain and spinal fluid

Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201 , USA.
Brain research (Impact Factor: 2.84). 12/2008; 1258:1-11. DOI: 10.1016/j.brainres.2008.12.047
Source: PubMed


The neuregulins are a family of polypeptide factors implicated in a wide range of neurological and psychiatric disorders including multiple sclerosis, schizophrenia, and Alzheimer's disease. Many alternatively-spliced forms of the NRG1 gene are released as soluble factors that can diffuse to near and distant sites within the nervous system where they can accumulate through binding to highly specific heparan-sulfate proteoglycans in the extracellular matrix. Here we have determined the sites of synthesis and accumulation of heparin-binding neuregulin forms in human neocortex, white matter, cerebral spinal fluid, and serum by immunostaining and measurement of neuregulin activity. While neuregulin precursors are expressed predominately within cortical neurons, soluble neuregulin accumulates preferentially on the surface of white matter astrocytes. Consistently, neuregulin activity can be released from the extracellular matrix of human brain by protease treatment. Neuregulin activity is also detectable in human cerebral spinal fluid where its expression appears to be altered in neuronal disorders. While cerebral spinal fluid neuregulin levels were unaltered in patients with multiple sclerosis, they were slightly reduced in amyotrophic lateral sclerosis and Parkinson's disease (p<0.15), but significantly increased in Alzheimer's disease (p<0.01). While not detected in human serum, a novel neuregulin antagonist activity was identified in human serum that could have prevented its detection. These results suggest that human neuregulin is selectively targeted from cortical neurons to white matter extracellular matrix where it exists in steady-state equilibrium with cerebral spinal fluid where it has the potential to serve as a biological marker in human neuronal disorders.

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    • "CSF insulin-like growth factor-1 (IGF-1) and IGF binding proteins (IGFBPs) expression is increased in PD patients (Mashayekhi et al., 2010). Finally, a single study found a non-significant trend toward increased CSF levels of neuroregulins (which belong to the Epidermal Growth Factor or EGF family) in PD patients (Pankonin et al., 2009). The results of studies on growth and neurotrophic factors in PD, involving a low number of patients and controls, do not permit definitive conclusions. "
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    Frontiers in Cellular Neuroscience 11/2014; fncel.2014.00369. eCollection 2014.. DOI:10.3389/fncel.2014.00369 · 4.29 Impact Factor
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    • "We did find significantly increased β EGF containing NRG1 protein within the dorsal horn using an ELISA following SNL. Cultured neurons have been shown to release soluble NRG1 in an activity dependent manner (Ozaki et al., 2004) and NRG1 activity has also been detected in human cerebrospinal fluid (Pankonin et al., 2009). In culture systems NRG1 activity has also been shown to be released from DRG cell axons (Esper and Loeb, 2004; Taveggia et al., 2005); this release is enhanced by BDNF (which is itself released by microglia following nerve injury (Coull et al., 2005)). "
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    ABSTRACT: A key component in the response of the nervous system to injury is the proliferation and switch to a "proinflammatory" phenotype by microglia (microgliosis). In situations where the blood-brain barrier is intact, microglial numbers increase via the proliferation and chemotaxis of resident microglia; however, there is limited knowledge regarding the factors mediating this response. After peripheral nerve injury, a dorsal horn microgliosis develops, which directly contributes to the development of neuropathic pain. Neuregulin-1 (NRG-1) is a growth and differentiation factor with a well characterized role in neural and cardiac development. Microglia express the NRG1 receptors erbB2, 3, and 4, and NRG1 signaling via the erbB2 receptor stimulated microglial proliferation, chemotaxis, and survival, as well as interleukin-1beta release in vitro. Intrathecal treatment with NRG1 resulted in microglial proliferation within the dorsal horn, and these cells developed an activated morphology. This microglial response was associated with the development of both mechanical and cold pain-related hypersensitivity. Primary afferents express NRG1, and after spinal nerve ligation (SNL) we observed both an increase in NRG1 within the dorsal horn as well as activation of erbB2 specifically within microglia. Blockade of the erbB2 receptor or sequestration of endogenous NRG after SNL reduced the proliferation, the number of microglia with an activated morphology, and the expression of phospho-P38 by microglia. Furthermore, consequent to such changes, the mechanical pain-related hypersensitivity and cold allodynia were reduced. NRG1-erbB signaling therefore represents a novel pathway regulating the injury response of microglia.
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