Department of Pharmacology, Yale University, New Haven, CT 06520, USA.
Mol Cell Neurosci. 2013 Sep;56:102-14. doi: 10.1016/j.mcn.2013.04.003. Epub 2013 Apr 24.
Chromogranin B (CGB) is a high capacity, low affinity calcium binding protein in the endoplasmic reticulum (ER) that binds to the inositol 1,4,5 trisphosphate receptor (InsP3R) and amplifies calcium release from ER stores. Recently, it was discovered that levels of CGB-derived peptides are decreased in the cerebrospinal fluid of multiple sclerosis (MS) patients. One of the mechanisms by which neurodegeneration in MS is thought to occur is through increased levels of intra-axonal calcium. The combination of excess intracellular calcium and dysregulated levels of CGB in MS led us to hypothesize that CGB may be involved in MS pathophysiology. Here, we show in a mouse model of MS that CGB levels are elevated in neurons prior to onset of symptoms. Once symptoms develop, CGB protein levels increase with disease severity. Additionally, we show that elevated levels of CGB may have a role in the pathophysiology of MS and suggest that the initial elevation of CGB, prior to symptom onset, is due to inflammatory processes. Upon development of symptoms, CGB accumulation in neurons results from decreased ubiquitination and decreased secretion. Furthermore, we show that calpain activity is increased and levels of InsP3R are decreased. From these results, we suggest that the elevated levels of CGB and altered InsP3R levels may contribute to the axonal/neuronal damage and dysregulated calcium homeostasis observed in MS. Additionally, we propose that CGB can be a biomarker that predicts the onset and severity of disease in patients with MS.
嗜铬粒蛋白 B（CGB）是内质网中一种高容量、低亲和力的钙结合蛋白，它与肌醇 1,4,5 三磷酸受体（InsP3R）结合并放大内质网储存钙的释放。最近，研究发现多发性硬化症（MS）患者脑脊液中的 CGB 衍生肽水平降低。MS 中神经退行性变的一种机制是通过轴内钙水平升高。MS 中细胞内钙过多和 CGB 水平失调的组合使我们假设 CGB 可能参与 MS 病理生理学。在这里，我们在 MS 的小鼠模型中显示，在症状出现之前，神经元中的 CGB 水平升高。一旦出现症状，CGB 蛋白水平就会随着疾病的严重程度而增加。此外，我们还表明，CGB 水平升高可能在 MS 的病理生理学中起作用，并表明在症状出现之前 CGB 的最初升高是由于炎症过程。出现症状后，神经元中 CGB 的积累是由于泛素化减少和分泌减少所致。此外，我们还表明钙蛋白酶活性增加，InsP3R 水平降低。根据这些结果，我们认为 CGB 水平升高和 InsP3R 水平改变可能导致 MS 中观察到的轴突/神经元损伤和钙稳态失调。此外，我们提出 CGB 可以作为预测 MS 患者疾病发作和严重程度的生物标志物。
