Strang Kevin H, Sorrentino Zachary A, Riffe Cara J, Gorion Kimberly-Marie M, Vijayaraghavan Niran, Golde Todd E, Giasson Benoit I
Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA.
Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32610, USA; McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
Neurosci Lett. 2019 Jan 23;692:187-192. doi: 10.1016/j.neulet.2018.11.011. Epub 2018 Nov 10.
Alzheimer's disease and other tauopathies are characterized by the brain accumulation of hyperphosphorylated aggregated tau protein forming pathological inclusions. Although elevated tau phosphorylated at many amino acid residues is a hallmark of pathological tau, some evidence suggest that tau phosphorylation at unique sites, especially within its microtubule-binding domain, might inhibit aggregation. In this study, the effects of phosphorylation of two unique residues within this domain, serine 305 (S305) and serine 320 (S320), were examined in the context of established aggregation and seeding models. It was found that the S305E phosphomimetic significantly inhibited both tau seeding and tau aggregation in this model, while S320E did not. To further explore S305 phosphorylation in vivo, a monoclonal antibody (2G2) specific for tau phosphorylated at S305 was generated and characterized. Consistent with inhibition of tau aggregation, phosphorylation of S305 was not detected in pathological tau inclusions in Alzheimer's disease brain tissue. This study indicates that phosphorylation of unique tau residues can be inhibitory to aggregate formation, and has important implications for potential kinase therapies. Additionally, it creates new tools for observing these changes in vivo.
阿尔茨海默病和其他tau蛋白病的特征是大脑中过度磷酸化的聚集tau蛋白积累，形成病理性包涵体。尽管许多氨基酸残基处磷酸化的tau蛋白水平升高是病理性tau蛋白的一个标志，但一些证据表明，tau蛋白在独特位点的磷酸化，尤其是在其微管结合域内的磷酸化，可能会抑制聚集。在本研究中，在已建立的聚集和种子模型背景下，研究了该结构域内两个独特残基丝氨酸305（S305）和丝氨酸320（S320）磷酸化的影响。发现在该模型中，模拟磷酸化的S305E显著抑制tau蛋白种子形成和tau蛋白聚集，而S320E则没有。为了进一步在体内探索S305磷酸化，制备并表征了一种对S305处磷酸化的tau蛋白具有特异性的单克隆抗体（2G2）。与tau蛋白聚集的抑制作用一致，在阿尔茨海默病脑组织的病理性tau蛋白包涵体中未检测到S305的磷酸化。本研究表明，tau蛋白独特残基的磷酸化可抑制聚集体形成，对潜在的激酶治疗具有重要意义。此外，它为在体内观察这些变化创造了新工具。
