Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
Capio St. Göran Hospital, 112 19 Stockholm, Sweden.
Int J Mol Sci. 2021 Nov 11;22(22):12193. doi: 10.3390/ijms222212193.
Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and similar neurodegenerative disorders take their toll on patients, caregivers and society. A common denominator for these disorders is the accumulation of aggregated proteins in nerve cells, yet the triggers for these aggregation processes are currently unknown. In ALS, protein aggregation has been described for the SOD1, C9orf72, FUS and TDP-43 proteins. The latter is a nuclear protein normally binding to both DNA and RNA, contributing to gene expression and mRNA life cycle regulation. TDP-43 seems to have a specific role in ALS pathogenesis, and ubiquitinated and hyperphosphorylated cytoplasmic inclusions of aggregated TDP-43 are present in nerve cells in almost all sporadic ALS cases. ALS pathology appears to include metal imbalances, and environmental metal exposure is a known risk factor in ALS. However, studies on metal-to-TDP-43 interactions are scarce, even though this protein seems to have the capacity to bind to metals. This review discusses the possible role of metals in TDP-43 aggregation, with respect to ALS pathology.
肌萎缩侧索硬化症（ALS）、阿尔茨海默病、帕金森病和类似的神经退行性疾病给患者、护理人员和社会带来了沉重的负担。这些疾病的一个共同特征是神经细胞中聚集蛋白的积累，但目前尚不清楚这些聚集过程的触发因素是什么。在 ALS 中，已经描述了 SOD1、C9orf72、FUS 和 TDP-43 蛋白的蛋白聚集。后者是一种正常结合 DNA 和 RNA 的核蛋白，有助于基因表达和 mRNA 生命周期调节。TDP-43 在 ALS 的发病机制中似乎具有特定的作用，并且在几乎所有散发性 ALS 病例的神经细胞中都存在聚集的 TDP-43 的泛素化和过度磷酸化的细胞质包涵体。ALS 病理学似乎包括金属失衡，环境金属暴露是 ALS 的已知危险因素。然而，关于金属与 TDP-43 相互作用的研究很少，尽管这种蛋白质似乎有结合金属的能力。本文讨论了金属在 TDP-43 聚集中的可能作用，以及其与 ALS 病理学的关系。
