Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada.
Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
Biomolecules. 2024 Jan 31;14(2):173. doi: 10.3390/biom14020173.
Calcium dyshomeostasis is an early critical event in neurodegeneration as exemplified by Alzheimer's (AD), Huntington's (HD) and Parkinson's (PD) diseases. Neuronal calcium homeostasis is maintained by a diversity of ion channels, buffers, calcium-binding protein effectors, and intracellular storage in the endoplasmic reticulum, mitochondria, and lysosomes. The function of these components and compartments is impacted by the toxic hallmark proteins of AD (amyloid beta and Tau), HD (huntingtin) and PD (alpha-synuclein) as well as by interactions with downstream calcium-binding proteins, especially calmodulin. Each of the toxic hallmark proteins (amyloid beta, Tau, huntingtin, and alpha-synuclein) binds to calmodulin. Multiple channels and receptors involved in calcium homeostasis and dysregulation also bind to and are regulated by calmodulin. The primary goal of this review is to show the complexity of these interactions and how they can impact research and the search for therapies. A secondary goal is to suggest that therapeutic targets downstream from calcium dyshomeostasis may offer greater opportunities for success.
钙稳态失调是神经退行性变的早期关键事件，如阿尔茨海默病（AD）、亨廷顿病（HD）和帕金森病（PD）。神经元钙稳态由多种离子通道、缓冲剂、钙结合蛋白效应物以及内质网、线粒体和溶酶体中的细胞内储存来维持。这些成分和隔室的功能受到 AD（β淀粉样蛋白和 Tau）、HD（亨廷顿蛋白）和 PD（α-突触核蛋白）的毒性标志性蛋白以及与下游钙结合蛋白（特别是钙调蛋白）相互作用的影响。每种毒性标志性蛋白（β淀粉样蛋白、Tau、亨廷顿蛋白和α-突触核蛋白）都与钙调蛋白结合。参与钙稳态和失调的多个通道和受体也与钙调蛋白结合并受其调节。本综述的主要目的是展示这些相互作用的复杂性，以及它们如何影响研究和治疗方法的寻找。次要目标是表明钙稳态失调下游的治疗靶点可能提供更大的成功机会。
