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      Using Drosophila as an integrated model to study mild repetitive traumatic brain injury

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          Abstract

          Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. In addition, there has been a growing appreciation that even repetitive, milder forms of TBI (mTBI) can have long-term deleterious consequences to neural tissues. Hampering our understanding of genetic and environmental factors that influence the cellular and molecular responses to injury has been the limited availability of effective genetic model systems that could be used to identify the key genes and pathways that modulate both the acute and long-term responses to TBI. Here we report the development of a severe and mild-repetitive TBI model using Drosophila. Using this system, key features that are typically found in mammalian TBI models were also identified in flies, including the activation of inflammatory and autophagy responses, increased Tau phosphorylation and neuronal defects that impair sleep-related behaviors. This novel injury paradigm demonstrates the utility of Drosophila as an effective tool to validate genetic and environmental factors that influence the whole animal response to trauma and to identify prospective therapies needed for the treatment of TBI.

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          Guidelines for the use and interpretation of assays for monitoring autophagy.

          C N Estevez, S M Lee, Qing Zhong … (2012)
          In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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            Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila.

            Michael Rera, Rebecca I. Clark, David W Walker (2012)
            Aging is characterized by a growing risk of disease and death, yet the underlying pathophysiology is poorly understood. Indeed, little is known about how the functional decline of individual organ systems relates to the integrative physiology of aging and probability of death of the organism. Here we show that intestinal barrier dysfunction is correlated with lifespan across a range of Drosophila genotypes and environmental conditions, including mitochondrial dysfunction and dietary restriction. Regardless of chronological age, intestinal barrier dysfunction predicts impending death in individual flies. Activation of inflammatory pathways has been linked to aging and age-related diseases in humans, and an age-related increase in immunity-related gene expression has been reported in Drosophila. We show that the age-related increase in expression of antimicrobial peptides is tightly linked to intestinal barrier dysfunction. Indeed, increased antimicrobial peptide expression during aging can be used to identify individual flies exhibiting intestinal barrier dysfunction. Similarly, intestinal barrier dysfunction is more accurate than chronological age in identifying individual flies with systemic metabolic defects previously linked to aging, including impaired insulin/insulin-like growth factor signaling, as evidenced by a reduction in Akt activation and up-regulation of dFOXO target genes. Thus, the age-dependent loss of intestinal integrity is associated with altered metabolic and immune signaling and, critically, is a harbinger of death. Our findings suggest that intestinal barrier dysfunction may be an important factor in the pathophysiology of aging in other species as well, including humans.
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              Recurrent concussion and risk of depression in retired professional football players.

              Kevin M. Guskiewicz, Stephen Marshall, Julian Edwin Bailes … (2007)
              The purpose of our study was to investigate the association between prior head injury and the likelihood of being diagnosed with clinical depression among retired professional football players with prior head injury exposure. A general health questionnaire, including information about prior injuries, the SF-36 (Short Form 36), and other markers for depression, was completed by 2552 retired professional football players with an average age of 53.8 (+/-13.4) yr and an average professional football-playing career of 6.6 (+/-3.6) yr. A second questionnaire focusing on mild cognitive impairment (MCI)-related issues was completed by a subset of 758 retired professional football players (50 yr and older). Two hundred sixty-nine (11.1%) of all respondents reported having prior or current diagnosis of clinical depression. There was an association between recurrent concussion and diagnosis of lifetime depression (chi2=71.21, df=2, P<0.005), suggesting that the prevalence increases with increasing concussion history. Compared with retired players with no history of concussion, retired players reporting three or more previous concussions (24.4%) were three times more likely to be diagnosed with depression; those with a history of one or two previous concussions (36.3%) were 1.5 times more likely to be diagnosed with depression. The analyses controlled for age, number of years since retirement, number of years played, physical component score on the SF-36, and diagnosed comorbidities such as osteoarthritis, coronary heart disease, stroke, cancer, and diabetes. Our findings suggest a possible link between recurrent sport-related concussion and increased risk of clinical depression. The findings emphasize the importance of understanding potential neurological consequences of recurrent concussion.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 04 May 2016
                Publication date Collection: 2016
                Volume: 6
                Electronic Location Identifier: 25252
                Affiliations
                [1 ]Donald P. Shiley BioScience Center, San Diego State University , San Diego, CA, USA
                [2 ]Department of Biology, San Diego State University , San Diego, CA, USA
                [3 ]Department of Pharmacology, University of California San Diego , La Jolla, CA, USA
                [4 ]Shock, Trauma, and Anesthesiology Research (STAR) Center; Department of Anesthesiology, University of Maryland School of Medicine , Baltimore, MD, USA
                [5 ]Department of Chemistry, San Diego State University , San Diego, CA, USA
                Author notes
                Article
                Publisher Item ID: srep25252
                DOI: 10.1038/srep25252
                PMC ID: 4855207
                PubMed ID: 27143646
                SO-VID: 2c5b5764-5acb-4e33-a4d6-1e9c46ea03b4
                Copyright © Copyright © 2016, Macmillan Publishers Limited
                License:

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                Date received : 07 December 2015
                Date accepted : 13 April 2016
                Categories
                Subject: Article

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