Brain trauma and autophagy: What flies and mice can teach us about conserved responses

Abstract

Drosophila models have been successfully used to identify many genetic components that affect neurodegenerative disorders. Recently, there has been a growing interest in identifying innate and environmental factors that influence the individual outcomes following traumatic brain injury (TBI). This includes both severe TBI and more subtle, mild TBI (mTBI), which is common in people playing contact sports. Autophagy, as a clearance pathway, exerts protective effects in multiple neurological disease models. In a recent publication, we highlighted the development of a novel repetitive mTBI system using Drosophila, which recapitulates several phenotypes associated with trauma in mammalian models. In particular, flies subjected to mTBI exhibit an acute impairment of the macroautophagy/autophagy pathway that is restored 1 wk following traumatic injury exposure. These phenotypes closely resemble temporary autophagy defects observed in a mouse TBI model. Through these studies, we also identified methods to directly assess autophagic responses in the fly nervous system and laid the groundwork for future studies designed to identify genetic, epigenetic and environmental factors that have an impact on TBI outcomes.

Loss of the Antimicrobial Peptide Metchnikowin Protects Against Traumatic Brain Injury Outcomes in Drosophila melanogaster

“…We found that TBI in flies shares key characteristics with TBI in mammals, including temporary incapacitation, short-term ataxia, progressive neurodegeneration, intestinal barrier dysfunction, hyperglycemia, and shortened lifespan ( Katzenberger et al 2013 , 2015a ). Furthermore, consistent with findings of an activated Nuclear Factor kappa B (NF-κB) response in mammals, transcriptional gene targets of the homologous NF-κB-mediated Toll and Immune-deficiency (Imd) signaling pathways are rapidly and persistently activated following TBI in multiple fly models ( Katzenberger et al 2013 , 2015a , 2015b 2016; Barekat et al 2016 ; Ratliff et al 2016 ; Sen et al 2017 ; Shah et al 2019 ). For example, expression of major Toll and Imd gene targets, antimicrobial peptides (AMPs), substantially increases within 30 min after TBI and remains elevated for at least 24 h ( Katzenberger et al 2016 ).…”

“…In flies, both closed-head and penetrating TBI leads to increased expression of AMP genes in fly heads ( Katzenberger et al 2016 ; Ratliff et al 2016 ; Sanuki et al 2019 ). However, the source of this expression is not known because fly heads contain multiple cell types, including neurons, glia, and fat body, all of which are known to express AMPs ( Cao et al 2013 ; Kounatidis et al 2017 ).…”

Roles of autophagy and endoplasmic reticulum stress in intracerebral hemorrhage‐induced secondary brain injury in rats

“…Neuronal damage and apoptosis are important pathological process in SBI after ICH. It has also been shown that autophagy is activated after ICH and endoplasmic reticulum (ER) stress occur in neurodegenerative diseases . And autophagy may play different role36s in ischemic and hemorrhagic stroke .…”

Effects of hyperbaric oxygen therapy on neuropathic pain via mitophagy in microglia

“… 6 , 7 ROS are also important factors in autophagy. 8 Although research has shown that cellular autophagy can lead to neurodegeneration or neuronal dysfunction, 9 the molecular mechanisms of neuropathic pain are still unknown.…”