Ataxia Telangiectasia triggers deficits in Reelin pathway

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.