Amyotrophic lateral sclerosis (ALS) is characterized by death and dysfunction of motor neurons that result in a rapidly progressing loss of motor function. While there are some data on alterations at the blood–brain barrier (BBB) in ALS and their potential impact on CNS trafficking of drugs, little is reported on the impact of this disease on the expression of drug-handling proteins in the small intestine and liver. This may impact the dosing of the many medicines that individuals with ALS are prescribed. In the present study, a proteomic evaluation was performed on small intestine and liver samples from postnatal day 120 SOD1^G93A mice (a model of familial ALS that harbors a human mutant form of superoxide dismutase 1) and wild-type (WT) littermates (n = 7/genotype/sex). Untargeted, quantitative proteomics was undertaken using either label-based [tandem mass tag (TMT)] or label-free [data-independent acquisition (DIA)] acquisition strategies on high-resolution mass spectrometric instrumentation. Copper chaperone for superoxide dismutase (CCS) was significantly higher in SOD1^G93A samples compared to the WT samples for both sexes and tissues, therefore representing a potential biomarker for ALS in this mouse model. Relative to WT mice, male SOD1^G93A mice had significantly different proteins (P_adj < 0.05, |fold-change|>1.2) in the small intestine (male 22, female 1) and liver (male 140, female 3). This included an up-regulation of intestinal transporters for dietary glucose [solute carrier (SLC) SLC5A1] and cholesterol (Niemann-Pick c1-like 1), as well as for several drugs (e.g., SLC15A1), in the male SOD1^G93A mice. There was both an up-regulation (e.g., SLCO2A1) and down-regulation (ammonium transporter rh type b) of transporters in the male SOD1^G93A liver. In addition, there was both an up-regulation (e.g., phosphoenolpyruvate carboxykinase) and down-regulation (e.g., carboxylesterase 1) of metabolizing enzymes in the male SOD1^G93A liver. This proteomic data set identified male-specific changes to key small intestinal and hepatic transporters and metabolizing enzymes that may have important implications for the bioavailability of nutrients and drugs in individuals with ALS.

中文翻译：

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肌萎缩侧索硬化症 SOD1G93A 小鼠模型中药物转运蛋白和代谢酶的肠道和肝脏丰度的性别依赖性变化

肌萎缩侧索硬化症 (ALS) 的特点是运动神经元死亡和功能障碍，导致运动功能迅速丧失。虽然有一些关于 ALS 中血脑屏障 (BBB) 变化及其对中枢神经系统药物贩运的潜在影响的数据，但很少有关于这种疾病对小肠和药物处理蛋白表达的影响的报道。肝。这可能会影响 ALS 患者所开的多种药物的剂量。在本研究中，对出生后 120 天的 SOD1 ^G93A小鼠（一种携带超氧化物歧化酶 1 人类突变型的家族性 ALS 模型）和野生型 (WT) 同窝小鼠的小肠和肝脏样本进行了蛋白质组学评估。= 7/基因型/性别）。在高分辨率质谱仪器上使用基于标记的[串联质量标签 (TMT)] 或无标记的[数据独立采集 (DIA)] 采集策略进行非靶向定量蛋白质组学。与 WT 样本相比， SOD1 ^G93A样本中超氧化物歧化酶 (CCS) 的铜伴侣无论性别还是组织均显着较高，因此代表了该小鼠模型中 ALS 的潜在生物标志物。相对于 WT 小鼠，雄性 SOD1 ^G93A小鼠在小肠（雄性 22 只，雌性 1 只）和肝脏（雄性 140 只，雌性 3 只）中具有显着不同的蛋白质（P _adj < 0.05，|倍数变化|> 1.2）。这包括雄性 SOD1 ^G93A小鼠中膳食葡萄糖 [溶质载体 (SLC) SLC5A1] 和胆固醇 (Niemann-Pick c1-like 1) 以及多种药物 (例如 SLC15A1) 的肠道转运蛋白的上调。雄性 SOD1 ^G93A肝脏中的转运蛋白同时存在上调（例如 SLCO2A1）和下调（铵转运蛋白 rh b 型）。此外，雄性SOD1 ^G93A肝脏中的代谢酶同时存在上调（例如磷酸烯醇丙酮酸羧激酶）和下调（例如羧酸酯酶1）。该蛋白质组数据集确定了关键小肠和肝脏转运蛋白和代谢酶的男性特异性变化，这些变化可能对 ALS 患者的营养素和药物的生物利用度产生重要影响。