Department of Neurology, University Medical Center Göttingen, and German Center for Neurodegenerative Diseases (DZNE), Robert Koch Strasse 40, 37075, Göttingen, Germany.
German Center for Neurodegenerative Diseases (DZNE), Translational Studies and Biomarkers, Site Göttingen, Germany.
Acta Neuropathol Commun. 2017 Apr 27;5(1):35. doi: 10.1186/s40478-017-0431-y.
Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrP). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis.Here we describe the presence of massive regulation of Ca responsive genes in sCJD brain tissue, accompanied by two Ca-dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain proteins activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Additionally, Calpain 1 treatment enhances seeding activity of PrP in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons, although massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model.Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention.
散发性克雅氏病（sCJD）是最常见的人类朊病毒病，其特征是神经元丧失、海绵状变性、慢性炎症和错误折叠的致病性朊病毒蛋白（PrP）的积累。这些改变的分子机制在很大程度上尚不清楚，但在朊病毒病模型中存在细胞内神经元钙（Ca）超载，这是普遍存在的特征，被认为在朊病毒发病机制中起关键作用。在这里，我们描述了 sCJD 脑组织中大量调节钙反应基因的存在，伴随着两个 Ca 依赖性过程：内质网应激和半胱氨酸蛋白酶 Calpain 1/2 的激活。sCJD 中致病性 Calpain 蛋白的激活与它们的细胞底物的切割、自噬受损和溶酶体损伤有关，在细胞朊病毒模型中，Calpain 抑制可部分逆转这些损伤。此外，Calpain 1 处理可增强 PrP 在朊病毒转化测定中的接种活性。Calpain 过度激活引起的神经元溶酶体损伤导致溶酶体蛋白酶组织蛋白酶 S 的释放，尽管在 sCJD 中主要在轴突中检测到大量组织蛋白酶 S 的过度表达，但在 microglial 细胞中也检测到大量组织蛋白酶 S 的过度表达。钙动态平衡的改变和 Calpain-Cathepsin 轴的激活已经在疾病的临床前阶段发生，这在人类 sCJD 小鼠模型中得到了检测。总之，我们的工作表明，Calpain-Cathepsin 激活的不平衡是 sCJD 在多个分子水平上发病机制的一个重要贡献因素，也是治疗干预的潜在靶点。
