UK Dementia Research Institute, Department of Clinical Neuroscience, University of Cambridge, Cambridge, CB2 0AH, UK.
Open Targets, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
Cell Death Differ. 2021 Jun;28(6):1804-1821. doi: 10.1038/s41418-020-00705-8. Epub 2020 Dec 17.
Mitochondria-ER contact sites (MERCS) are known to underpin many important cellular homoeostatic functions, including mitochondrial quality control, lipid metabolism, calcium homoeostasis, the unfolded protein response and ER stress. These functions are known to be dysregulated in neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD) and amyloid lateral sclerosis (ALS), and the number of disease-related proteins and genes being associated with MERCS is increasing. However, many details regarding MERCS and their role in neurodegenerative diseases remain unknown. In this review, we aim to summarise the current knowledge regarding the structure and function of MERCS, and to update the field on current research in PD, AD and ALS. Furthermore, we will evaluate high-throughput screening techniques, including RNAi vs CRISPR/Cas9, pooled vs arrayed formats and how these could be combined with current techniques to visualise MERCS. We will consider the advantages and disadvantages of each technique and how it can be utilised to uncover novel protein pathways involved in MERCS dysfunction in neurodegenerative diseases.
线粒体-内质网接触位点（MERCS）已知是许多重要的细胞内稳态功能的基础，包括线粒体质量控制、脂质代谢、钙稳态、未折叠蛋白反应和内质网应激。这些功能在神经退行性疾病中被认为是失调的，包括帕金森病（PD）、阿尔茨海默病（AD）和淀粉样侧索硬化症（ALS），并且与 MERCS 相关的疾病相关蛋白和基因的数量正在增加。然而，关于 MERCS 及其在神经退行性疾病中的作用的许多细节仍然未知。在这篇综述中，我们旨在总结关于 MERCS 的结构和功能的现有知识，并更新关于 PD、AD 和 ALS 中当前研究的领域。此外，我们将评估高通量筛选技术，包括 RNAi 与 CRISPR/Cas9、pooled 与 arrayed 格式，以及如何将这些技术与当前的可视化 MERCS 技术相结合。我们将考虑每种技术的优缺点，以及如何利用它来发现参与神经退行性疾病中 MERCS 功能障碍的新的蛋白途径。
