Ataxia telangiectasia alters the ApoB and 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 ataxiatelangiectasiamutated (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, protocadherinfat 2, sempahorin 7A, and increased apolipoprotein Band 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 reelinfrom glutamatergic afferent axons is crucial for PN lipoprotein receptor endocytosis and lipid signaling. Reelinexpression 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 reelinreceptors Apoer2/Vldlr with increases for their ligands Apoe/Apoh and cholesterol 24-hydroxylaseCyp46a1. Concomitant dysregulations were found for Vglut2/Sema7a as climbing fibermarkers, 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 reelinsignaling deficits reflect the neurodegenerationin 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.