O'Day Danton H
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada.
Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.
Int J Mol Sci. 2024 Dec 14;25(24):13424. doi: 10.3390/ijms252413424.
The predominant neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are rarely pure diseases but, instead, show a diversity of mixed pathologies. At some level, all of them share a combination of one or more different toxic biomarker proteins: amyloid beta (Aβ), phosphorylated Tau (pTau), alpha-synuclein (αSyn), mutant huntingtin (mHtt), fused in sarcoma, superoxide dismutase 1, and TAR DNA-binding protein 43. These toxic proteins share some common attributes, making them potentially universal and simultaneous targets for therapeutic intervention. First, they all form toxic aggregates prior to taking on their final forms as contributors to plaques, neurofibrillary tangles, Lewy bodies, and other protein deposits. Second, the primary enzyme that directs their aggregation is transglutaminase 2 (TGM2), a brain-localized enzyme involved in neurodegeneration. Third, TGM2 binds to calmodulin, a regulatory event that can increase the activity of this enzyme threefold. Fourth, the most common mixed pathology toxic biomarkers (Aβ, pTau, αSyn, nHtt) also bind calmodulin, which can affect their ability to aggregate. This review examines the potential therapeutic routes opened up by this knowledge. The end goal reveals multiple opportunities that are immediately available for universal therapeutic treatment of the most devastating neurodegenerative diseases facing humankind.
主要的神经退行性疾病，如阿尔茨海默病、帕金森病、路易体痴呆、亨廷顿舞蹈病、肌萎缩侧索硬化症和额颞叶痴呆，很少是单纯的疾病，而是呈现出多种混合病理状态。在某种程度上，它们都存在一种或多种不同的毒性生物标志物蛋白的组合：β-淀粉样蛋白（Aβ）、磷酸化tau蛋白（pTau）、α-突触核蛋白（αSyn）、突变型亨廷顿蛋白（mHtt）、肉瘤融合蛋白、超氧化物歧化酶1和TAR DNA结合蛋白43。这些毒性蛋白具有一些共同特性，使其有可能成为治疗干预的通用且同时的靶点。首先，它们在形成最终形式（如斑块、神经原纤维缠结、路易小体和其他蛋白质沉积物）之前都会形成毒性聚集体。其次，指导它们聚集的主要酶是转谷氨酰胺酶2（TGM2），这是一种参与神经退行性变的脑定位酶。第三，TGM2与钙调蛋白结合，这一调节事件可使该酶的活性增加三倍。第四，最常见的混合病理毒性生物标志物（Aβ、pTau、αSyn、nHtt）也与钙调蛋白结合，这可能会影响它们的聚集能力。本综述探讨了这一知识所开辟的潜在治疗途径。最终目标揭示了多个可立即用于普遍治疗人类面临的最具破坏性神经退行性疾病的机会。
