Ataxia Telangiectasia triggers deficits in Reelin pathway

Abstract

Autosomal recessive Ataxia Telangiectasia (A-T) is characterized by radiosensitivity, immunodeficiency and cerebellar neurodegeneration. A-T is caused by inactivating mutations in the Ataxia-Telangiectasia-Mutated (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, -H, -J peptides.Bioinformatic enrichment was observed for pathways of chemical response, locomotion, calcium binding and complement immunity. This seemed important, since secretion of Reelin from glutamatergic afferent axons is crucial for PN radial migration and spine homeostasis. Reelin expression is downregulated by irradiation and its deficiency is a known cause of ataxia. Validation efforts in 2-month-old Atm-/-mice before onset of motor deficits confirmed 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.These findings show that deficient levels of Reelin signaling factors reflect the neurodegeneration in A-T in a sensitive and specific way. As an extracellular factor, Reelin may be accessible for neuroprotective interventions.3 Keywords:Ataxia Telangiectasia, label-free mass spectrometry, diagnostic biomarkers, Reelin 4 while no elevation of oxidative stress markers TBARS, CAT, SOD was detected [14]. A re-analysis of this question in model organisms upon the first description of Atm-/-mice has emphasized that affected organs are targets of ROS-mediated damage, in particular the cerebellar PN [15]. The prominent role of oxidative stress for the deficient survival and dendritogenesis of PN was independently confirmed in Atm-/-mice [16].Accumulation of DNA damage, alterations of the redox status and deficient calciumdependent excitability in the brains of Atm-/-mice could be demonstrated [17][18][19].However, these investigations are hampered by the early death of Atm-/-mice by the age of 4-6 months due to thymic lymphomas, at a stage when their cerebellum appears histologically normal and the mice have no relevant movement deficit [20]. Only when their survival is extended to ages around 8 months by bone-marrow transplantation, a significant cerebellar atrophy with reduced numbers of PN becomes apparent by magnetic resonance imaging and calbindin-immunohistochemistry [21].To identify further molecular biomarkers of risk and progression in A-T in the extracellular fluid, we studied cerebrospinal flu...