Molecular Neurology Group, Hospital Nacional de Parapléjicos (HNP), Finca la Peraleda s/n, 45071, Toledo, Spain.
Department of Pathology and Experimental Therapeutics, Service of Pathologic Anatomy, IDIBELL-Bellvitge University Hospital, CIBERNED, Hospitalet de Llobregat, University of Barcelona, Barcelona, Spain.
Mol Neurobiol. 2019 Oct;56(10):6777-6791. doi: 10.1007/s12035-019-1547-9. Epub 2019 Mar 28.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with no cure, and elucidation of the mechanisms mediating neuronal death in this neuropathology is crucial to develop effective treatments. It has recently been demonstrated in animal models that the Wnt family of proteins is involved in this neuropathology, although its potential involvement in case of humans is almost unknown. We analyzed the expression of Wnt signaling components in healthy and ALS human spinal cords by quantitative RT-PCR, and we found that most Wnt ligands, modulators, receptors, and co-receptors were expressed in healthy controls. Moreover, we observed clear alterations in the mRNA expression of different components of this family of proteins in human spinal cord tissue from ALS cases. Specifically, we detected a significant increase in the mRNA levels of Wnt3, Wnt4, Fz2, and Fz8, together with several non-significant increases in the mRNA expression of other genes such as Wnt2b, Wnt5a, Fz3, Lrp5, and sFRP3. Based on these observations and on previous reports of studies performed in animal models, we evaluated with immunohistochemistry the protein expression patterns of Fz2 and Fz5 receptors and their main ligand Wnt5a in control samples and ALS cases. No substantial changes were observed in Fz5 protein expression pattern in ALS samples. However, we detected an increase in the amount of Fz2+ astrocytes in the borderline between gray and white matter at the ventral horn in ALS samples. Finally, Wnt5a expression was observed in neurons and astrocytes in both control and ALS samples, although Wnt5a immunolabeling in astroglial cells was significantly increased in ALS spinal cords in the same region where changes in Fz2 were observed. Altogether, these observations strongly suggest that the Wnt family of proteins, and more specifically Fz2 and Wnt5a, might be involved in human ALS pathology.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，目前尚无治愈方法，阐明介导这种神经病理学中神经元死亡的机制对于开发有效的治疗方法至关重要。最近在动物模型中已经证明，Wnt 蛋白家族参与了这种神经病理学，尽管其在人类病例中的潜在作用几乎未知。我们通过定量 RT-PCR 分析了健康和 ALS 人脊髓中 Wnt 信号成分的表达，发现大多数 Wnt 配体、调节剂、受体和共受体在健康对照中表达。此外，我们观察到人类脊髓组织中这种蛋白质家族的不同成分的 mRNA 表达发生了明显变化。具体而言，我们检测到 Wnt3、Wnt4、Fz2 和 Fz8 的 mRNA 水平显著增加，而其他基因如 Wnt2b、Wnt5a、Fz3、Lrp5 和 sFRP3 的 mRNA 表达也有几个非显著增加。基于这些观察结果以及动物模型研究的先前报告，我们用免疫组织化学评估了 Fz2 和 Fz5 受体及其主要配体 Wnt5a 在对照样本和 ALS 病例中的蛋白表达模式。在 ALS 样本中，Fz5 蛋白表达模式没有明显变化。然而，我们在 ALS 样本的腹角灰质和白质交界处检测到 Fz2+星形胶质细胞数量增加。最后，我们在对照和 ALS 样本中均观察到 Wnt5a 在神经元和星形胶质细胞中的表达，尽管在 ALS 脊髓中同一区域观察到 Fz2 变化时，星形胶质细胞中的 Wnt5a 免疫标记显著增加。总之，这些观察结果强烈表明 Wnt 蛋白家族，特别是 Fz2 和 Wnt5a，可能参与了人类 ALS 病理学。
