Spruill Maria M, Kuncl Ralph W
Department of Neurology and Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
J Neurosci Res. 2015 Aug;93(8):1184-91. doi: 10.1002/jnr.23562. Epub 2015 Apr 24.
Slow glutamate-mediated neuronal degeneration is implicated in the pathophysiology of motor neuron diseases such as amyotrophic lateral sclerosis (ALS). The calcium-binding proteins calbindin-D28K and parvalbumin have been reported to protect neurons against excitotoxic insults. Expression of calbindin-D28K is low in adult human motor neurons, and vulnerable motor neurons additionally may lack parvalbumin. Thus, it has been speculated that the lack of calcium-binding proteins may, in part, be responsible for early degeneration of the population of motor neurons most vulnerable in ALS. Using a rat organotypic spinal cord slice system, we examined whether the most potent neuroprotective factors for motor neurons can increase the expression of calbindin-D28K or parvalbumin proteins in the postnatal spinal cord. After 4 weeks of incubation of spinal cord slices with 1) glial cell line-derived neurotrophic factor (GDNF), 2) neurturin, 3) insulin-like growth factor I (IGF-I), or 4) pigment epithelium-derived factor (PEDF), the number of calbindin-D28K -immunopositive large neurons (>20 μm) in the ventral horn was higher under the first three conditions, but not after PEDF, compared with untreated controls. Under the same conditions, parvalbumin was not upregulated by any neuroprotective factor. The same calbindin increase was true of IGF-I and GDNF in a parallel glutamate toxicity model of motor neuron degeneration. Taken together with our previous reports from the same model, which showed that all these neurotrophic factors can potently protect motor neurons from slow glutamate injury, the data here suggest that upregulation of calbindin-D28K by some of these factors may be one mechanism by which motor neurons can be protected from glutamate-induced, calcium-mediated excitotoxicity.
缓慢的谷氨酸介导的神经元变性与运动神经元疾病如肌萎缩侧索硬化症（ALS）的病理生理学有关。据报道，钙结合蛋白钙结合蛋白-D28K和小白蛋白可保护神经元免受兴奋性毒性损伤。钙结合蛋白-D28K在成体人类运动神经元中的表达较低，而易损运动神经元可能还缺乏小白蛋白。因此，有人推测钙结合蛋白的缺乏可能部分导致了ALS中最易受损的运动神经元群体的早期变性。我们使用大鼠脊髓器官型切片系统，研究了对运动神经元最有效的神经保护因子是否能增加出生后脊髓中钙结合蛋白-D28K或小白蛋白的表达。将脊髓切片与1）胶质细胞系源性神经营养因子（GDNF）、2）神经营养素、3）胰岛素样生长因子I（IGF-I）或4）色素上皮衍生因子（PEDF）孵育4周后，与未处理的对照组相比，在前三种条件下，腹角中钙结合蛋白-D28K免疫阳性的大神经元（>20μm）数量增加，但在PEDF处理后未增加。在相同条件下，任何神经保护因子均未上调小白蛋白。在运动神经元变性的平行谷氨酸毒性模型中，IGF-I和GDNF也出现了相同的钙结合蛋白增加情况。结合我们之前从同一模型得出的报告，即所有这些神经营养因子都能有效保护运动神经元免受缓慢的谷氨酸损伤，此处的数据表明，其中一些因子上调钙结合蛋白-D28K可能是运动神经元免受谷氨酸诱导的、钙介导的兴奋性毒性损伤的一种机制。
