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Ataxia telangiectasia alters the ApoB and reelin pathway

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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 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.

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Acknowledgements

We thank Dr. Suzana Gispert-Sánchez and Katrin Krug for advice and technical assistance. We are also grateful to Konrad Bochennek for the collection of the CSF samples and give many thanks to Ramona Mayer from the DKFZ Protein Analysis Core Facility for sample preparation for mass spectrometry.

Funding

This research received funding from the A-T Children’s Project.

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Author notes

  1. Stefan Zielen and Uwe Warnken contributed equally to this work.

Authors and Affiliations

  1. Exp. Neurology, Goethe University Medical School, 60590, Frankfurt am Main, Germany

    Júlia Canet-Pons & Georg Auburger

  2. Division for Allergy, Pneumology and Cystic Fibrosis, Department for Children and Adolescents, Goethe University, 60590, Frankfurt am Main, Germany

    Ralf Schubert, Ruth Pia Duecker, Roland Schrewe, Sandra Wölke & Stefan Zielen

  3. Division for Neurology, Department for Children and Adolescents, Goethe University, 60590, Frankfurt am Main, Germany

    Matthias Kieslich & Uwe Warnken

  4. Functional Proteome Analysis, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany

    Martina Schnölzer

  5. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe University Medical School, 60528, Frankfurt am Main, Germany

    Andreas Chiocchetti

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Electronic supplementary material

Suppl. Fig. 1

Proteomic analysis of the Cerebro-Spinal Fluid (CSF) from 11 A-T patients (age 4–16 years) and 9 controls (age 1–17 years), performed by a label-free protein quantification approach using nano ultra-high performance liquid chromatography/ nano electrospray mass spectrometry (nano UPLC/ nanoESI-MS). Analysis of the data was performed with the MaxQuant and Perseus quantitative proteomics softwares. Correlation between protein label-free quantitation and age is shown for (A) Reelin, (B) Calbindin, (C) cerebellin-3, (D) cerebellin-1, (E) Apolipoprotein B100, and (F) Clusterin/ApoJ. (PNG 222 kb)

High Resolution Image (TIF 17216 kb)

Suppl. Fig. 2

Changes in Reelin signaling in relation to age and to the ataxia score. Correlation of (A) Reelin LFQ values with ataxia scores and (B) correlation of the RELN/TotalProtein ratios with age in 11 A-T patients. Correlations were assessed by calculating Pearson’s correlation coefficient. (PNG 73 kb)

High Resolution Image (TIF 5463 kb)

Suppl. Fig 3

Coimmunofluorescent studies of cerebellum from ~2-month-old Atm−/− versus WT mice, displaying the immunoreactivity of (A) Reelin vs. Calbindin, (B) ApoB vs. Calbindin, (C) VLDLR vs. Calbindin. (PNG 2398 kb)

High Resolution Image (TIF 17228 kb)

Suppl. Table 1

Linear interaction model of protein label-free quantitation values from CSF and age in patients with A-T (n = 11) vs. control individuals (n = 9). (DOCX 20 kb)

Suppl. Table 2

Biomathematical analysis of pathway enrichments among the molecular dysregulations in the CSF proteome of the 3 oldest A-T patients. (XLS 44 kb)

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Canet-Pons, J., Schubert, R., Duecker, R.P. et al. Ataxia telangiectasia alters the ApoB and reelin pathway. Neurogenetics 19, 237–255 (2018). https://doi.org/10.1007/s10048-018-0557-5

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