Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
School of Biochemistry, University of Bristol, Bristol, UK.
J Pathol. 2020 Jul;251(3):262-271. doi: 10.1002/path.5455. Epub 2020 Jun 8.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. The majority of cases are sporadic (sALS), while the most common inherited form is due to C9orf72 mutation (C9ALS). A high burden of inclusion pathology is seen in glia (including oligodendrocytes) in ALS, especially in C9ALS. Myelin basic protein (MBP) messenger RNA (mRNA) must be transported to oligodendrocyte processes for myelination, a possible vulnerability for normal function. TDP43 is found in pathological inclusions in ALS and is a component of mRNA transport granules. Thus, TDP43 aggregation could lead to MBP loss. Additionally, the hexanucleotide expansion of mutant C9ALS binds hnRNPA2/B1, a protein essential for mRNA transport, causing potential further impairment of hnRNPA2/B1 function, and thus myelination. Using immunohistochemistry for p62 and TDP43 in human post-mortem tissue, we found a high burden of glial inclusions in the prefrontal cortex, precentral gyrus, and spinal cord in ALS, which was greater in C9ALS than in sALS cases. Double staining demonstrated that the majority of these inclusions were in oligodendrocytes. Using immunoblotting, we demonstrated reduced MBP protein levels relative to PLP (a myelin component that relies on protein not mRNA transport) and neurofilament protein (an axonal marker) in the spinal cord. This MBP loss was disproportionate to the level of PLP and axonal loss, suggesting that impaired mRNA transport may be partly responsible. Finally, we show that in C9ALS cases, the level of oligodendroglial inclusions correlates inversely with levels of hnRNPA2/B1 and the number of oligodendrocyte precursor cells. We conclude that there is considerable oligodendrocyte pathology in ALS, which at least partially reflects impairment of mRNA transport. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病。大多数病例为散发性（sALS），而最常见的遗传性形式是由于 C9orf72 突变（C9ALS）引起的。在 ALS 中，胶质细胞（包括少突胶质细胞）中可见包涵体病理学负担较高，尤其是在 C9ALS 中。髓鞘碱性蛋白（MBP）信使 RNA（mRNA）必须运输到少突胶质细胞的突起中进行髓鞘形成，这可能是正常功能的一个脆弱点。TDP43 存在于 ALS 的病理学包涵体中，是 mRNA 运输颗粒的组成部分。因此，TDP43 聚集可能导致 MBP 丢失。此外，突变型 C9ALS 的六核苷酸扩展与 hnRNPA2/B1 结合，hnRNPA2/B1 是 mRNA 运输所必需的一种蛋白质，导致 hnRNPA2/B1 功能的潜在进一步损伤，从而导致髓鞘形成受损。使用针对人死后组织中的 p62 和 TDP43 的免疫组织化学染色，我们发现在 ALS 的前额叶皮层、中央前回和脊髓中存在大量的神经胶质包涵体，在 C9ALS 病例中比在 sALS 病例中更多。双染色表明，这些包涵体中的大多数存在于少突胶质细胞中。通过免疫印迹法，我们证明与髓鞘成分 PLP（依赖于蛋白质而不是 mRNA 运输的蛋白）和神经丝蛋白（轴突标志物）相比，脊髓中的 MBP 蛋白水平降低。这种 MBP 丢失与 PLP 和轴突丢失不成比例，表明受损的 mRNA 运输可能部分负责。最后，我们发现 C9ALS 病例中的少突胶质细胞包涵体水平与 hnRNPA2/B1 水平和少突胶质细胞前体细胞数量呈负相关。我们得出结论，在 ALS 中有相当多的少突胶质细胞病理学，这至少部分反映了 mRNA 运输的受损。© 2020 作者。John Wiley & Sons Ltd 代表英国和爱尔兰病理学学会出版的《病理学杂志》。
