Laboratory of Structural Neuropathology, Doshisha University Graduate School of Brain Science, 1-3 Miyakodanitatara, Kyotanabe-shi, Kyoto, 610-0394, Japan.
Department of Neuroscience of Disease, Brain Research Institute, Niigata University, Niigata, Japan.
Sci Rep. 2022 Mar 14;12(1):4347. doi: 10.1038/s41598-022-08044-z.
Intrinsically disordered proteins (IDPs) have been in the spotlight for their unique properties, such as their lack of secondary structures and low sequence complexity. Alpha-synuclein and tau are representative disease-related IDPs with low complexity regions in their sequences, accumulating in the brains of patients with Parkinson disease and Alzheimer disease, respectively. Their heat resistance in particular was what attracted our attention. We assumed that there exist many other unidentified proteins that are resistant to heat-treatment, referred to as heat-stable proteins, which would also have low sequence complexity. In this study, we performed proteomic analysis of heat-stable proteins of mouse brains and found that proteins with compositionally biased regions are abundant in the heat-stable proteins. The proteins related to neurodegeneration are known to undergo different types of post-translational modifications (PTMs) such as phosphorylation and ubiquitination. We then investigated the heat-stability and aggregation properties of phosphorylated synuclein and tau with different phosphorylation sites. We suggest that PTMs can be important factors that determine the heat-stability and aggregation properties of a protein. IDPs identified in the heat-stable proteins of mouse brains would be candidates for the pathogenic proteins for neurodegeneration.
无规则蛋白质（IDPs）因其独特的性质而备受关注，例如它们缺乏二级结构和低序列复杂度。α-突触核蛋白和 tau 是具有代表性的疾病相关 IDPs，它们的序列中存在低复杂度区域，分别在帕金森病和阿尔茨海默病患者的大脑中积累。它们的耐热性特别引起了我们的注意。我们假设存在许多其他未被识别的对热处理有抗性的蛋白质，称为热稳定蛋白质，它们也具有低序列复杂度。在这项研究中，我们对小鼠大脑的热稳定蛋白质进行了蛋白质组学分析，发现组成上偏向区域的蛋白质在热稳定蛋白质中丰富。已知与神经退行性变相关的蛋白质会经历不同类型的翻译后修饰（PTMs），如磷酸化和泛素化。然后，我们研究了具有不同磷酸化位点的磷酸化 synuclein 和 tau 的热稳定性和聚集特性。我们认为 PTMs 可以是决定蛋白质热稳定性和聚集特性的重要因素。在小鼠大脑的热稳定蛋白质中鉴定出的 IDPs 可能是神经退行性变致病蛋白的候选者。
