Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, 2 Technology Place, NSW 2109, Australia..
Neurobiol Dis. 2022 May;166:105653. doi: 10.1016/j.nbd.2022.105653. Epub 2022 Feb 7.
Investigations into the pathogenetic mechanisms underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have provided significant insight into the disease. At the cellular level, ALS and FTD are classified as proteinopathies, which is motor neuron degeneration and death characterized by pathological protein aggregates or dysregulated proteostasis. At both the clinical and molecular level there are common signaling pathways dysregulated across the ALS and FTD spectrum (ALS/FTD). Sequestosome-1/p62 is a multifunctional scaffold protein with roles in several signaling pathways including proteostasis, protein degradation via the ubiquitin proteasome system and autophagy, the antioxidant response, inflammatory response, and apoptosis. Notably these pathways are dysregulated in ALS and FTD. Mutations in the functional domains of p62 provide links to the pathogenetic mechanisms of p62 and dyshomeostasis of p62 levels is noted in several types of ALS and FTD. We present here that the dysregulated ALS and FTD signaling pathways are linked, with p62 converging the molecular mechanisms. This review summarizes the current literature on the complex role of p62 in the pathogenesis across the ALS/FTD spectrum. The focus is on the underlying convergent molecular mechanisms of ALS and FTD-associated proteins and pathways that dysregulate p62 levels or are dysregulated by p62, with emphasis on how p62 is implicated across the ALS/FTD spectrum.
对肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 发病机制的研究为该疾病提供了重要的见解。在细胞水平上，ALS 和 FTD 被归类为蛋白质病，其特征是运动神经元退行性变和死亡，伴有病理性蛋白质聚集体或失调的蛋白稳态。在临床和分子水平上，ALS 和 FTD 谱（ALS/FTD）中都存在共同的信号通路失调。自噬体相关蛋白 1（sequestosome-1，p62）是一种多功能支架蛋白，在包括蛋白稳态、通过泛素蛋白酶体系统和自噬进行蛋白质降解、抗氧化反应、炎症反应和细胞凋亡在内的几种信号通路中发挥作用。值得注意的是，这些通路在 ALS 和 FTD 中失调。p62 的功能域突变提供了与 p62 发病机制的联系，并且在几种类型的 ALS 和 FTD 中都注意到 p62 水平的失调。我们在这里提出，失调的 ALS 和 FTD 信号通路是相关的，p62 汇聚了分子机制。这篇综述总结了目前关于 p62 在 ALS/FTD 谱中发病机制中的复杂作用的文献。重点是 ALS 和 FTD 相关蛋白和通路的潜在汇聚分子机制，这些蛋白和通路会失调 p62 水平或被 p62 失调，重点是 p62 如何在 ALS/FTD 谱中涉及。
