Neurogenetics Group, Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK.
J Cell Mol Med. 2020 Jun;24(11):6055-6069. doi: 10.1111/jcmm.15170. Epub 2020 Apr 23.
Amyotrophic lateral sclerosis (ALS) is a disorder that affects motor neurons in motor cortex and spinal cord, and the degeneration of both neuronal populations is a critical feature of the disease. Abnormalities in protein homeostasis (proteostasis) are well established in ALS. However, they have been investigated mostly in spinal cord but less so in motor cortex. Herein, we monitored the unfolded protein (UPR) and heat shock response (HSR), two major proteostasis regulatory pathways, in human post-mortem tissue derived from the motor cortex of sporadic ALS (SALS) and compared them to those occurring in spinal cord. Although the UPR was activated in both tissues, specific expression of select UPR target genes, such as PDIs, was observed in motor cortex of SALS cases strongly correlating with oligodendrocyte markers. Moreover, we found that endoplasmic reticulum-associated degradation (ERAD) and HSR genes, which were activated predominately in spinal cord, correlated with the expression of neuronal markers. Our results indicate that proteostasis is strongly and selectively activated in SALS motor cortex and spinal cord where subsets of these genes are associated with specific cell type. This study expands our understanding of convergent molecular mechanisms occurring in motor cortex and spinal cord and highlights cell type-specific contributions.
肌萎缩侧索硬化症（ALS）是一种影响运动皮层和脊髓运动神经元的疾病，这两种神经元群体的退化是该疾病的一个关键特征。蛋白质平衡（蛋白稳态）异常在 ALS 中得到了很好的证实。然而，这些异常主要在脊髓中进行了研究，而在运动皮层中研究较少。在此，我们监测了 unfolded protein (UPR) 和 heat shock response (HSR)，这两种主要的蛋白稳态调节途径，在源自散发性 ALS (SALS)的运动皮层的人类死后组织中，并将其与脊髓中的情况进行了比较。虽然 UPR 在两种组织中都被激活，但在 SALS 病例的运动皮层中观察到特定 UPR 靶基因（如 PDIs）的特异性表达，这与少突胶质细胞标志物强烈相关。此外，我们发现主要在脊髓中激活的内质网相关降解 (ERAD) 和 HSR 基因与神经元标志物的表达相关。我们的结果表明，蛋白稳态在 SALS 运动皮层和脊髓中被强烈且选择性地激活，其中这些基因的某些亚类与特定细胞类型相关。这项研究扩展了我们对运动皮层和脊髓中发生的趋同分子机制的理解，并强调了细胞类型特异性的贡献。
