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Ataxia telangiectasia alters the ApoB and reelin pathway.
Neurogenetics ( IF 2.2 ) Pub Date : 2018-10-21 , DOI: 10.1007/s10048-018-0557-5
Júlia Canet-Pons 1 , Ralf Schubert 2 , Ruth Pia Duecker 2 , Roland Schrewe 2 , Sandra Wölke 2 , Matthias Kieslich 3 , Martina Schnölzer 4 , Andreas Chiocchetti 5 , Georg Auburger 1 , Stefan Zielen 2 , Uwe Warnken 3
Affiliation  

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.

中文翻译:

共济失调毛细血管扩张改变了ApoB和reelin途径。

常染色体隐性共济失调毛细血管扩张症(AT)的特征是放射敏感性,免疫缺陷和小脑神经变性。AT是由共济失调毛细血管扩张突变(ATM)基因的失活引起的,该基因是一种参与DNA损伤反应和兴奋性神经传递的丝氨酸-苏氨酸蛋白激酶。小脑浦肯野神经元(PN)对AT的选择性脆弱性尚不十分清楚。通过对15岁左右患者的脑脊液进行蛋白质组学分析,我们检测到降钙素,瑞林,小脑1,小脑3,原钙粘蛋白脂肪2,sempahorin 7A减少,载脂蛋白B和J肽增加。在脂蛋白,内吞作用,细胞外基质受体相互作用,肽酶活性,粘附,钙结合,并补充免疫力。这似乎很重要,因为从谷氨酸能传入轴突中分泌瑞林对PN脂蛋白受体的内吞作用和脂质信号传导至关重要。Reelin表达被辐射下调,而reelin / ApoB突变是共济失调的已知原因。2个月大的验证工作运动障碍开始前的Atm -/-小鼠证实,reelin受体Apoer2 / Vldlr的小脑转录产物减少,配体Apoe / Apoh和胆固醇24-羟化酶Cyp46a1升高。同时发现Vglut2 / Sema7a失调是攀登纤维标记,谷氨酸受体如Grin2b和钙稳态因子(Atp2b2Calb1Itpr1),而与DNA损伤,氧化应激,神经炎症和细胞粘附有关的因素在此阶段是正常的。定量免疫印迹证实,在2个月大时,小脑组织中ApoB和ApoJ升高且VLDLR降低。这些发现表明,ApoB过量和reelin信号缺陷以敏感和特定的方式反映了AT中的神经变性。作为细胞外因子,载脂蛋白及其货物如维生素E可能对神经保护性干预有用。
更新日期:2018-10-21
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