Biology subjects

Schenck, A.

Publications and source records attributed to Schenck, A..

2 recordsLinked to original sources

bioRxiv2018

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.

neuroscience↗

bioRxiv2018

Integrative cross-species analyses identify deficits in habituation learning as a widely affected mechanism in Autism

BackgroundAlthough habituation is one of the most ancient and fundamental forms of learning, its regulators and relevance for human disease are poorly understood.\n\nMethodsWe manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested these models in light-off jump habituation. We dissected neuronal substrates underlying the identified habituation deficits and integrated genotype-phenotype annotations, gene ontologies and interaction networks to determine the clinical features and molecular processes that are associated with habituation deficits.\n\nResultsWe identified more than 100 genes required for habituation learning. For the vast majority of these, 93 genes, a role in habituation learning was previously unknown. These genes characterize ID disorders with overgrowth/macrocephaly and comorbid ASD. Moreover, ASD individuals from the Simons Simplex Collection carrying disruptive de novo mutations in these genes exhibit increased rates of specific aberrant behaviors including stereotypic speech, hyperactivity and irritability. At the molecular level, ID genes required for normal habituation are enriched in synaptic function and converge on Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK signaling in cholinergic neurons specifically inhibit the adaptive habituation response.\n\nConclusionsOur work demonstrates the relevance of habituation learning to autism, identifies an unprecedented number of novel habituation players, supports an emerging role for inhibitory neurons in habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK signaling. This establishes habituation as a possible, widely applicable target for pharmacologic intervention in ID/ASD.

neuroscience↗