Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada.
The Neuro's Early Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada.
Glia. 2024 Nov;72(11):2079-2094. doi: 10.1002/glia.24598. Epub 2024 Aug 2.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive death of motor neurons (MNs). Glial cells play roles in MN degeneration in ALS. More specifically, astrocytes with mutations in the ALS-associated gene Cu/Zn superoxide dismutase 1 (SOD1) promote MN death. The mechanisms by which SOD1-mutated astrocytes reduce MN survival are incompletely understood. To characterize the impact of SOD1 mutations on astrocyte physiology, we generated astrocytes from human induced pluripotent stem cell (iPSC) derived from ALS patients carrying SOD1 mutations, together with control isogenic iPSCs. We report that astrocytes harboring SOD1(A4V) and SOD1(D90A) mutations exhibit molecular and morphological changes indicative of reactive astrogliosis when compared to isogenic astrocytes. We show further that a number of nuclear phenotypes precede, or coincide with, reactive transformation. These include increased nuclear oxidative stress and DNA damage, and accumulation of the SOD1 protein in the nucleus. These findings reveal early cell-autonomous phenotypes in SOD1-mutated astrocytes that may contribute to the acquisition of a reactive phenotype involved in alterations of astrocyte-MN communication in ALS.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是运动神经元（MNs）的进行性死亡。神经胶质细胞在 ALS 中的 MN 变性中起作用。更具体地说，携带 ALS 相关基因铜/锌超氧化物歧化酶 1（SOD1）突变的星形胶质细胞促进 MN 死亡。SOD1 突变星形胶质细胞降低 MN 存活率的机制尚不完全清楚。为了描述 SOD1 突变对星形胶质细胞生理学的影响，我们从携带 SOD1 突变的 ALS 患者的人类诱导多能干细胞（iPSC）中生成了星形胶质细胞，以及对照同基因 iPSC。我们报告说，与同基因星形胶质细胞相比，携带 SOD1(A4V)和 SOD1(D90A)突变的星形胶质细胞表现出分子和形态变化，表明存在反应性星形胶质细胞增生。我们进一步表明，许多核表型先于或与反应性转化同时发生。这些包括核氧化应激和 DNA 损伤增加，以及 SOD1 蛋白在核内积累。这些发现揭示了 SOD1 突变星形胶质细胞中的早期细胞自主表型，这些表型可能有助于获得涉及 ALS 中星形胶质细胞-MN 通讯改变的反应性表型。
