Integrative Network and Brain Expression Analysis reveals Mechanistic Modules in Ataxia

Background: Genetic forms of ataxia are a heterogenous group of degenerative diseases of the cerebellum. Many causative genes have been identified, but a systematic investigation of these genes to understand ataxia pathophysiology has not been performed. 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 (GO), protein network, and brain gene expression profiling analysis. Results: We found that ataxia genes 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 overrepresented among ataxia genes and are enriched for ion homeostasis/synaptic functions. The majority of ataxia genes, 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 defense pathways against stress are more critical to maintain cerebellar integrity than integrity of other brain regions. Approximately half of the ataxia genes, 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 ROS levels, or mechanisms that can decrease the harmful downstream effects of these deleterious insults.