Vision Research Center, Department of Ophthalmology, School of Medicine, University of Missouri - Kansas City, Kansas City, MO, USA.
Exp Neurol. 2013 Dec;250:143-50. doi: 10.1016/j.expneurol.2013.09.001. Epub 2013 Sep 9.
Presenilins (PS), endoplasmic reticulum (ER) transmembrane proteins, form the catalytic core of γ-secretase, an amyloid precursor protein processing enzyme. Mutations in PS lead to Alzheimer's disease (AD) by altering γ-secretase activity to generate pathologic amyloid beta and amyloid plaques in the brain. Here, we identified a novel mechanism where binding of a soluble, cytosolic N-terminal domain fragment (NTF) of PS to intracellular Ca(2+) release channels, ryanodine receptors (RyR), controls Ca(2+) release from the ER. While PS1NTF decreased total RyR-mediated Ca(2+) release, PS2NTF had no effect at physiological Ca(2+) concentrations. This differential function and isotype-specificity is due to four cysteines absent in PS1NTF, present, however, in PS2NTF. Site-directed mutagenesis targeting these cysteines converted PS1NTF to PS2NTF function and vice versa, indicating differential RyR binding. This novel mechanism of intracellular Ca(2+) regulation through the PS-RyR interaction represents a novel target for AD drug development and the treatment of other neurodegenerative disorders that critically depend on RyR and PS signaling.
早老素（PS）是内质网（ER）跨膜蛋白，形成 γ-分泌酶的催化核心，γ-分泌酶是一种淀粉样前体蛋白加工酶。PS 的突变通过改变 γ-分泌酶的活性在大脑中产生病理淀粉样β和淀粉样斑块，从而导致阿尔茨海默病（AD）。在这里，我们发现了一种新的机制，即 PS 的可溶性细胞质 N 端结构域片段（NTF）与细胞内 Ca²⁺释放通道ryanodine 受体（RyR）结合，控制 ER 中的 Ca²⁺释放。虽然 PS1NTF 降低了总 RyR 介导的 Ca²⁺释放，但 PS2NTF 在生理 Ca²⁺浓度下没有作用。这种差异功能和同种型特异性是由于 PS1NTF 中缺少四个半胱氨酸，而 PS2NTF 中存在这些半胱氨酸。针对这些半胱氨酸的定点突变将 PS1NTF 转化为 PS2NTF 功能，反之亦然，表明 RyR 结合的差异。通过 PS-RyR 相互作用调节细胞内 Ca²⁺的这种新机制代表了 AD 药物开发和其他严重依赖 RyR 和 PS 信号的神经退行性疾病治疗的新靶点。
