Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University, Munich, Germany.
Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-University, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; German Center for Neurodegenerative Diseases, DZNE, Munich, Germany.
Ageing Res Rev. 2016 Dec;32:122-139. doi: 10.1016/j.arr.2016.04.008. Epub 2016 May 7.
Impaired protein degradation has been discussed as a cause or consequence of various neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's disease. More recently, evidence accumulated that dysfunctional protein degradation may play a role in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Since in almost all neurodegenerative diseases, protein aggregates are disease-defining hallmarks, it is most likely that impaired protein degradation contributes to disease onset and progression. In the majority of FTD cases, the pathological protein aggregates contain either microtubuleassociated protein tau or TAR DNA-binding protein (TDP)-43. Aggregates are also positive for ubiquitin and p62/sequestosome 1 (SQSTM1) indicating that these aggregates are targeted for degradation. FTD-linked mutations in genes encoding three autophagy adaptor proteins, p62/SQSTM1, ubiquilin 2 and optineurin, indicate that impaired autophagy might cause FTD. Furthermore, the strongest evidence for lysosomal impairment in FTD is provided by the progranulin (GRN) gene, which is linked to FTD and neuronal ceroid lipofuscinosis. In this review, we summarize the observations that have been made during the last years linking the accumulation of disease-associated proteins in FTD to impaired protein degradation pathways. In addition, we take resent findings for nucleocytoplasmic transport defects of TDP-43, as discussed for hexanucleotide repeat expansions in C9orf72 into account and provide a hypothesis how the interplay of altered nuclear transport and protein degradation leads to the accumulation of protein deposits.
蛋白质降解功能障碍已被认为是多种神经退行性疾病（如阿尔茨海默病、帕金森病和亨廷顿病）的病因或结果。最近的证据表明，蛋白质降解功能障碍可能在额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）中发挥作用。由于在几乎所有神经退行性疾病中，蛋白质聚集体都是疾病定义的特征，因此蛋白质降解功能障碍极有可能导致疾病的发生和发展。在大多数 FTD 病例中，病理性蛋白质聚集体含有微管相关蛋白 tau 或 TAR DNA 结合蛋白（TDP）-43。聚集体还对泛素和 p62/自噬体 1（SQSTM1）呈阳性，表明这些聚集体是降解的靶标。编码三种自噬衔接蛋白（p62/SQSTM1、泛素结合酶 2 和视神经萎缩蛋白）的基因中与 FTD 相关的突变表明，自噬功能障碍可能导致 FTD。此外，在 FTD 中溶酶体功能障碍的最强证据是由颗粒蛋白基因（GRN）提供的，该基因与 FTD 和神经元蜡样脂褐质沉积症有关。在这篇综述中，我们总结了近年来将 FTD 中与疾病相关的蛋白质积累与蛋白质降解途径受损联系起来的观察结果。此外，我们还考虑了 TDP-43 的核质转运缺陷的最新发现，正如 C9orf72 中的六核苷酸重复扩展所讨论的那样，并提供了一个假设，即核转运和蛋白质降解的改变如何相互作用导致蛋白质沉积的积累。
