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Original article
Integrative network and brain expression analysis reveals mechanistic modules in ataxia
  1. Ilse Eidhof1,
  2. Bart P van de Warrenburg2,
  3. Annette Schenck1
  1. 1Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands
  2. 2Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands
  1. Correspondence to Dr Bart P van de Warrenburg, Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud university medical centre, Nijmegen 6525GA, The Netherlands; Bart.vandeWarrenburg{at}radboudumc.nl and Dr Annette Schenck, Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Centre, Nijmegen 6525GC, The Netherlands; Annette.Schenck{at}radboudumc.nl

Abstract

Background Genetic forms of ataxia are a heterogenous group of degenerative diseases of the cerebellum. Many causative genes have been identified. We aimed to systematically investigate these genes to better understand ataxia pathophysiology.

Methods A manually curated catalogue of 71 genes involved in disorders with progressive ataxias as a major clinical feature was subjected to an integrated gene ontology, protein network and brain gene expression profiling analysis.

Results We found that genes mutated in ataxias operate in networks with significantly enriched protein connectivity, demonstrating coherence on a global level, independent of inheritance mode. Moreover, elevated expression specifically in the cerebellum predisposes to ataxia. Genes expressed in this pattern are significantly over-represented among genes mutated in ataxia and are enriched for ion homeostasis/synaptic functions. The majority of genes mutated in ataxia, however, does not show elevated cerebellar expression that could account for region-specific degeneration. For these, we identified defective cellular stress responses as a major common biological theme, suggesting that the defence pathways against stress are more critical to maintain cerebellar integrity than integrity of other brain regions. Approximately half of the genes mutated in ataxia, mostly part of the stress module, show higher expression at embryonic stages, which argues for a developmental predisposition.

Conclusion Genetic defects in ataxia predominantly affect neuronal homeostasis, to which the cerebellum appears to be excessively susceptible. Based on the identified modules, it is conceivable to propose common therapeutic interventions that target deregulated calcium and reactive oxygen species levels, or mechanisms that can decrease the harmful downstream effects of these deleterious insults.

  • movement disorders (other than parkinsons)
  • neurology
  • molecular genetics

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Footnotes

  • Patient consent for publication Not required.

  • Contributors All authors conceived the study. IE designed the analyses, collected, analysed and interpreted the data and drafted the manuscript. BPvdW contributed to the design of the gene list. BPvdW and AS interpreted the results, and critically reviewed the manuscript. All authors read and approved the final version of the manuscript.

  • Funding This research was supported by the E-RARE-3 Joint Transnational Call grant ’Preparing therapies for autosomal recessive ataxias' (PREPARE; ZonMW 9003037604 to BPvdW and AS) and by a Donders Center for medical Neuroscience/Radboud University Medical Center junior researcher grant.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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