Department of Neurosurgery, Clinical Neuroscience Center, Zurich University Hospital, Zurich University, Zurich, Switzerland.
Neuroscience Center Zurich (ZNZ), University of Zurich and ETH Zurich, Zurich, Switzerland.
Brain. 2019 Apr 1;142(4):885-902. doi: 10.1093/brain/awz032.
Brain calcifications are commonly detected in aged individuals and accompany numerous brain diseases, but their functional importance is not understood. In cases of primary familial brain calcification, an autosomally inherited neuropsychiatric disorder, the presence of bilateral brain calcifications in the absence of secondary causes of brain calcification is a diagnostic criterion. To date, mutations in five genes including solute carrier 20 member 2 (SLC20A2), xenotropic and polytropic retrovirus receptor 1 (XPR1), myogenesis regulating glycosidase (MYORG), platelet-derived growth factor B (PDGFB) and platelet-derived growth factor receptor β (PDGFRB), are considered causal. Previously, we have reported that mutations in PDGFB in humans are associated with primary familial brain calcification, and mice hypomorphic for PDGFB (Pdgfbret/ret) present with brain vessel calcifications in the deep regions of the brain that increase with age, mimicking the pathology observed in human mutation carriers. In this study, we characterize the cellular environment surrounding calcifications in Pdgfbret/ret animals and show that cells around vessel-associated calcifications express markers for osteoblasts, osteoclasts and osteocytes, and that bone matrix proteins are present in vessel-associated calcifications. Additionally, we also demonstrate the osteogenic environment around brain calcifications in genetically confirmed primary familial brain calcification cases. We show that calcifications cause oxidative stress in astrocytes and evoke expression of neurotoxic astrocyte markers. Similar to previously reported human primary familial brain calcification cases, we describe high interindividual variation in calcification load in Pdgfbret/ret animals, as assessed by ex vivo and in vivo quantification of calcifications. We also report that serum of Pdgfbret/ret animals does not differ in calcification propensity from control animals and that vessel calcification occurs only in the brains of Pdgfbret/ret animals. Notably, ossification of vessels and astrocytic neurotoxic response is associated with specific behavioural and cognitive alterations, some of which are associated with primary familial brain calcification in a subset of patients.
脑钙化在老年人中很常见，并且伴随着许多脑部疾病，但它们的功能重要性尚不清楚。在原发性家族性脑钙化的情况下，一种常染色体遗传性神经精神疾病，双侧脑钙化的存在而无脑钙化的继发性原因是一个诊断标准。迄今为止，包括溶质载体 20 成员 2（SLC20A2）、异嗜性和多瘤病毒受体 1（XPR1）、肌生成调节糖苷酶（MYORG）、血小板衍生生长因子 B（PDGFB）和血小板衍生生长因子受体β（PDGFRB）在内的五个基因的突变被认为是致病的。以前，我们已经报道过人类 PDGFB 突变与原发性家族性脑钙化有关，并且 PDGFB 功能降低的小鼠（Pdgfbret/ret）在大脑深部区域出现血管钙化，随着年龄的增长而增加，模拟了在人类突变携带者中观察到的病理学。在这项研究中，我们描述了 Pdgfbret/ret 动物中围绕钙化的细胞环境，并表明血管相关钙化周围的细胞表达成骨细胞、破骨细胞和成骨细胞的标志物，并且血管相关钙化中存在骨基质蛋白。此外，我们还在基因确认的原发性家族性脑钙化病例中证明了脑钙化周围的成骨环境。我们表明，钙化会在星形胶质细胞中引起氧化应激，并引发神经毒性星形胶质细胞标志物的表达。与以前报道的人类原发性家族性脑钙化病例相似，我们描述了 Pdgfbret/ret 动物中钙化负荷的个体间差异很大，通过对钙化的离体和体内定量来评估。我们还报告说，Pdgfbret/ret 动物的血清在钙化倾向方面与对照动物没有差异，并且只有在 Pdgfbret/ret 动物的大脑中才会发生血管钙化。值得注意的是，血管的骨化和星形胶质细胞的神经毒性反应与特定的行为和认知改变有关，其中一些与原发性家族性脑钙化在一部分患者中的发生有关。
