Genetic Modifiers Influencing the Acute and Long-Term Responses to Traumatic Brain Injury in Drosophila

ABSTRACT Worldwide, traumatic brain injury (TBI) represents a major cause of mortality and long-term disability, with even mild repetitive forms of TBI (mTBI) potentially having deleterious consequences for both the acute and long-term function of the nervous system. Understanding the key cellular and molecular processes that occur following TBI exposure and potential factors that influence individual injury responses has been limited in part by the lack of comprehensive in vivo screening technique that directly compares stress sensitive and resistant genotypes involving conserved genes and functional pathways. In this report, we use a high throughput adult Drosophila trauma model system to compare the impact modest insulin signaling (IRS/chico) and autophagic defects (Atg8a/MAPLC3, Ref(2)P/SQSM1) have on traumatic injury outcomes. Using both severe and mild repetitive injury conditions the acute mortality indexes, longevity profiles, molecular and behavioral changes (locomotor, sleep) for individual fly genotypes were assessed. Compared to control cohorts (w1118/+), heterozygous chico mutants (chico1/+) demonstrated resistance, while aged flies (+2-weeks) or autophagy mutants (Atg8a1, Ref(2)Pc/e, Ref(2)Pe/+) showed heightened trauma sensitivity. Alterations that promote or impair autophagic function, longevity and stress responses were examined. Overall, this injury paradigm illustrates the effectiveness of using model systems to characterize conserved genetic factors that influence neuronal autophagy during complex trauma response. It also raises the potential for developing unique screens and therapies for patients that have experienced TBI. Competing Interest Statement The authors have declared no competing interest. Abbreviations - TBI - traumatic brain injury - mTBI - mild repetitive TBI - sTBI - severe TBI - Genome-wide association studies - GWAS - Ref(2)P - Refractory to sigma P - SQSTM1 - Sequestosome-1 - AD - Alzheimer disease - ATG5 - autophagy related 5 - ATG7 - autophagy related 7 - ATG12 - autophagy related 12 - BECN1 - beclin 1, autophagy related - CCI - controlled cortical impact - MAP1LC3/LC3 - microtuble-associated protein - PE - diacyl glycerophosphatidylethanolamine - ROS - reactive oxygen species