Evans Harrison Tudor, Taylor Deonne, Kneynsberg Andrew, Bodea Liviu-Gabriel, Götz Jürgen
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia.
Acta Neuropathol Commun. 2021 Jun 19;9(1):110. doi: 10.1186/s40478-021-01208-4.
The synthesis of new proteins is a fundamental aspect of cellular life and is required for many neurological processes, including the formation, updating and extinction of long-term memories. Protein synthesis is impaired in neurodegenerative diseases including tauopathies, in which pathology is caused by aberrant changes to the microtubule-associated protein tau. We recently showed that both global de novo protein synthesis and the synthesis of select ribosomal proteins (RPs) are decreased in mouse models of frontotemporal dementia (FTD) which express mutant forms of tau. However, a comprehensive analysis of the effect of FTD-mutant tau on ribosomes is lacking. Here we used polysome profiling, de novo protein labelling and mass spectrometry-based proteomics to examine how ribosomes are altered in models of FTD. We identified 10 RPs which were decreased in abundance in primary neurons taken from the K3 mouse model of FTD. We further demonstrate that expression of human tau (hTau) decreases both protein synthesis and biogenesis of the 60S ribosomal subunit, with these effects being exacerbated in the presence of FTD-associated tau mutations. Lastly, we demonstrate that expression of the amino-terminal projection domain of hTau is sufficient to reduce protein synthesis and ribosomal biogenesis. Together, these data reinforce a role for tau in impairing ribosomal function.
新蛋白质的合成是细胞生命的一个基本方面，是许多神经过程所必需的，包括长期记忆的形成、更新和消退。在包括tau蛋白病在内的神经退行性疾病中，蛋白质合成受损，其中病理是由微管相关蛋白tau的异常变化引起的。我们最近发现，在表达突变形式tau的额颞叶痴呆（FTD）小鼠模型中，整体从头蛋白质合成和特定核糖体蛋白（RPs）的合成均减少。然而，缺乏对FTD突变型tau对核糖体影响的全面分析。在这里，我们使用多核糖体分析、从头蛋白质标记和基于质谱的蛋白质组学来研究FTD模型中核糖体是如何改变的。我们鉴定出10种核糖体蛋白，其在取自FTD的K3小鼠模型的原代神经元中的丰度降低。我们进一步证明，人tau（hTau）的表达会降低蛋白质合成和60S核糖体亚基的生物合成，在存在FTD相关tau突变的情况下，这些影响会加剧。最后，我们证明hTau的氨基末端突出结构域的表达足以降低蛋白质合成和核糖体生物合成。总之，这些数据强化了tau在损害核糖体功能中的作用。
