Dept. Biomedical Sciences, University of Cagliari, Monserrato, Italy.
Dept. Biomedical Sciences, University of Cagliari, Monserrato, Italy.
Neuroscience. 2018 Jun 1;380:152-163. doi: 10.1016/j.neuroscience.2018.03.023. Epub 2018 Mar 26.
While the VGF-derived TLQP peptides have been shown to prevent neuronal apoptosis, and to act on synaptic strengthening, their involvement in Amyotrophic Lateral Sclerosis (ALS) remains unclarified. We studied human ALS patients' plasma (taken at early to late disease stages) and primary fibroblast cultures (patients vs controls), in parallel with SOD1-G93A transgenic mice (taken at pre-, early- and late symptomatic stages) and the mouse motor neuron cell line (NSC-34) treated with Sodium Arsenite (SA) to induce oxidative stress. TLQP peptides were measured by enzyme-linked immunosorbent assay, in parallel with gel chromatography characterization, while their localization was studied by immunohistochemistry. In controls, TLQP peptides, including forms compatible with TLQP-21 and 62, were revealed in plasma and spinal cord motor neurons, as well as in fibroblasts and NSC-34 cells. TLQP peptides were reduced in ALS patients' plasma starting in the early disease stage (14% of controls) and remaining so at the late stage (16% of controls). In mice, a comparable pattern of reduction was shown (vs wild type), in both plasma and spinal cord already in the pre-symptomatic phase (about 26% and 70%, respectively). Similarly, the levels of TLQP peptides were reduced in ALS fibroblasts (31% of controls) and in the NSC-34 treated with Sodium Arsenite (53% of decrease), however, the exogeneous TLQP-21 improved cell viability (SA-treated cells with TLQP-21, vs SA-treated cells only: about 83% vs. 75%). Hence, TLQP peptides, reduced upon oxidative stress, are suggested as blood biomarkers, while TLQP-21 exerts a neuroprotective activity.
虽然 VGF 衍生的 TLQP 肽已被证明可防止神经元凋亡，并作用于突触强化，但它们在肌萎缩侧索硬化症（ALS）中的作用仍不清楚。我们研究了人类 ALS 患者的血浆（取自疾病早期至晚期）和原代成纤维细胞培养物（患者与对照组），同时研究了 SOD1-G93A 转基因小鼠（取自前、早和晚症状阶段）和用亚砷酸钠（SA）处理的小鼠运动神经元细胞系（NSC-34）以诱导氧化应激。通过酶联免疫吸附测定法测量 TLQP 肽，同时进行凝胶色谱分析，同时通过免疫组织化学研究其定位。在对照组中，TLQP 肽，包括与 TLQP-21 和 62 兼容的形式，在血浆和脊髓运动神经元中以及成纤维细胞和 NSC-34 细胞中均被揭示。从疾病早期阶段（对照组的 14%）开始，ALS 患者的血浆中 TLQP 肽减少，并在晚期阶段（对照组的 16%）保持不变。在小鼠中，已显示出类似的减少模式（与野生型相比），在血浆和脊髓中均在无症状前阶段（分别约为 26%和 70%）。同样，ALS 成纤维细胞（对照组的 31%）和用亚砷酸钠处理的 NSC-34 中的 TLQP 肽水平降低（减少约 53%），但是外源性 TLQP-21 可提高细胞活力（用 TLQP-21 处理的 SA 处理的细胞，与仅用 SA 处理的细胞相比：约 83%比 75%）。因此，提示氧化应激时减少的 TLQP 肽作为血液生物标志物，而 TLQP-21 发挥神经保护作用。
