Exp. Neurology, Goethe University Medical School, 60590, Frankfurt am Main, Germany.
Division for Allergy, Pneumology and Cystic Fibrosis, Department for Children and Adolescents, Goethe University, 60590, Frankfurt am Main, Germany.
Neurogenetics. 2018 Dec;19(4):237-255. doi: 10.1007/s10048-018-0557-5. Epub 2018 Oct 21.
Autosomal recessive ataxia telangiectasia (A-T) is characterized by radiosensitivity, immunodeficiency, and cerebellar neurodegeneration. A-T is caused by inactivating mutations in the ataxia telangiectasiamutated (ATM) gene, a serine-threonine protein kinase involved in DNA damage response and excitatory neurotransmission. The selective vulnerability of cerebellar Purkinje neurons (PN) to A-T is not well understood. Employing global proteomic profiling of cerebrospinal fluid from patients at ages around 15 years, we detected reduced calbindin, reelin, cerebellin-1, cerebellin-3, protocadherin fat 2, sempahorin 7A, and increased apolipoprotein B and J peptides. Bioinformatic enrichment was observed for pathways of lipoproteins, endocytosis, extracellular matrix receptor interaction, peptidase activity, adhesion, calcium binding, and complement immunity. This seemed important since secretion of reelin from glutamatergic afferent axons is crucial for PN lipoprotein receptor endocytosis and lipid signaling. Reelin expression is downregulated by irradiation and reelin/ApoB mutations are known causes of ataxia. Validation efforts in 2-month-old Atm-/- mice before onset of motor deficits confirmed cerebellar transcript reductions for reelin receptors Apoer2/Vldlr with increases for their ligands Apoe/Apoh and cholesterol 24-hydroxylase Cyp46a1. Concomitant dysregulations were found for Vglut2/Sema7a as climbing fiber markers, glutamate receptors like Grin2b, and calcium homeostasis factors (Atp2b2, Calb1, Itpr1), while factors involved in DNA damage, oxidative stress, neuroinflammation, and cell adhesion were normal at this stage. Quantitative immunoblots confirmed ApoB and ApoJ increases and VLDLR reduction in cerebellar tissue at the age of 2 months. These findings show that ApoB excess and reelin signaling deficits reflect the neurodegeneration in A-T in a sensitive and specific way. As extracellular factors, apolipoproteins and their cargo such as vitamin E may be useful for neuroprotective interventions.
常染色体隐性遗传共济失调毛细血管扩张症（A-T）的特征是对辐射敏感、免疫缺陷和小脑神经退行性变。A-T 是由共济失调毛细血管扩张症突变（ATM）基因失活突变引起的，该基因是一种丝氨酸-苏氨酸蛋白激酶，参与 DNA 损伤反应和兴奋性神经递质传递。小脑浦肯野神经元（PN）对 A-T 的选择性易损性尚不清楚。我们通过对年龄在 15 岁左右的患者脑脊液进行全蛋白质组学分析，发现钙结合蛋白、reelin、小脑肽-1、小脑肽-3、原钙黏蛋白 fat2、sempahorin 7A 减少，载脂蛋白 B 和 J 肽增加。生物信息学富集观察到脂蛋白、内吞作用、细胞外基质受体相互作用、肽酶活性、黏附、钙结合和补体免疫等途径。这似乎很重要，因为谷氨酸能传入轴突分泌的 reelin 对于 PN 脂蛋白受体的内吞作用和脂质信号转导至关重要。reelin 的表达受照射下调，reelin/ApoB 突变是共济失调的已知原因。在运动功能障碍发作前的 2 月龄 Atm-/-小鼠中进行的验证工作证实，reelin 受体 Apoer2/Vldlr 的小脑转录物减少，其配体 Apoe/Apoh 和胆固醇 24-羟化酶 Cyp46a1 增加。同时发现作为 climbing fiber 标志物的 Vglut2/Sema7a、谷氨酸受体如 Grin2b 和钙稳态因子（Atp2b2、Calb1、Itpr1）的失调，而在此阶段，参与 DNA 损伤、氧化应激、神经炎症和细胞黏附的因子正常。定量免疫印迹证实 2 月龄时小脑组织中 ApoB 和 ApoJ 增加和 VLDLR 减少。这些发现表明，ApoB 过量和 reelin 信号缺陷以敏感和特异的方式反映了 A-T 中的神经退行性变。作为细胞外因子，载脂蛋白及其 cargo（如维生素 E）可能对神经保护干预有用。
