Defective Phagocytic Corpse Processing Results in Neurodegeneration and Can Be Rescued by TORC1 Activation

Abstract

The removal of apoptotic cell corpses is important for maintaining homeostasis. Previously, defects in apoptotic cell clearance have been linked to neurodegeneration. However, the mechanisms underlying this are still poorly understood. In this study, we report that the absence of the phagocytic receptor Draper in glia leads to a pronounced accumulation of apoptotic neurons in the brain of Drosophila melanogaster. These dead cells persist in the brain throughout the lifespan of the organism and are associated with age-dependent neurodegeneration. Our data indicate that corpses persist because of defective phagosome maturation, rather than recognition defects. TORC1 activation, or inhibition of Atg1, in glia is sufficient to rescue corpse accumulation as well as neurodegeneration. These results suggest that phagocytosis of apoptotic neurons by glia during development is essential for brain homeostasis in adult flies. Furthermore, it suggests that TORC1 regulates Draper-mediated phagosome maturation.

Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging

“…Similarly, genetic manipulations of phagocytosis in the fruit fly Drosophila melanogaster also demonstrate the impact of engulfment of apoptotic cells to aging and neurodegeneration. For instance, deletion of the phagocytic receptor Draper leads to developmental accumulation of apoptotic neurons, which persist undegraded throughout the lifespan and induce neurodegeneration with increased age [114]. Genetic screening of engulfment- and/or degradation-related phagocytic receptors indicates that glial phagocytic defects and the persistence of apoptotic bodies in Drosophila brain are associated with dysfunctional phagosome maturation rather than with impaired engulfment [114].…”

“…For instance, deletion of the phagocytic receptor Draper leads to developmental accumulation of apoptotic neurons, which persist undegraded throughout the lifespan and induce neurodegeneration with increased age [114]. Genetic screening of engulfment- and/or degradation-related phagocytic receptors indicates that glial phagocytic defects and the persistence of apoptotic bodies in Drosophila brain are associated with dysfunctional phagosome maturation rather than with impaired engulfment [114]. Moreover, phagocytosis in Drosophila ’s brain may be similar to LAP described in macrophages, as TORC1 activation (a fruit fly protein homologous to mammalian MTORC1) or inhibition of ATG1 (a fruit fly protein homologous to mammalian ULK-1), which may inhibit autophagy flux, prevents apoptotic cell body induced neurodegeneration [114], suggesting that classical autophagy inhibition may enable translocation of the autophagosome formation machinery to LAP.…”

“…Genetic screening of engulfment- and/or degradation-related phagocytic receptors indicates that glial phagocytic defects and the persistence of apoptotic bodies in Drosophila brain are associated with dysfunctional phagosome maturation rather than with impaired engulfment [114]. Moreover, phagocytosis in Drosophila ’s brain may be similar to LAP described in macrophages, as TORC1 activation (a fruit fly protein homologous to mammalian MTORC1) or inhibition of ATG1 (a fruit fly protein homologous to mammalian ULK-1), which may inhibit autophagy flux, prevents apoptotic cell body induced neurodegeneration [114], suggesting that classical autophagy inhibition may enable translocation of the autophagosome formation machinery to LAP. In conclusion, these results suggest that autophagy inhibition may enable a LAP-like mechanism in invertebrate glial cells that promotes correct lysosomal processing of apoptotic cells and prevents neurodegeneration.…”

Insulin-like Signaling Promotes Glial Phagocytic Clearance of Degenerating Axons through Regulation of Draper

“…Drosophila is a powerful model for investigating fundamental aspects of neurodegeneration and glial responses to neural damage (Ayaz et al, 2008; Cantera and Barrio, 2015; Etchegaray et al, 2016; Fang and Bonini, 2012; Freeman et al, 2003; Kato et al, 2011; Lee and Sun, 2015; Logan and Freeman, 2007; Liu et al, 2015; Mishra et al, 2013; Rooney and Freeman, 2014; Ugur et al, 2016). Axotomy in adult flies elicits glial reactions that share many cellular hallmarks with mammalian glia responding to neurodegeneration, including altered morphology and increased phagocytic function (Kurant 2011; Logan and Freeman, 2007).…”

Glial contributions to neuronal health and disease: new insights from Drosophila

“…In Drosophila , Draper is also required for glial engulfment of degenerating axons after acute nerve axotomy in adults (23, 27, 29, 30). Notably, neurodegeneration occurs in aged draper mutant animals (31, 32), and this phenotype is rescued by glial expression of target of rapamycin 1 (TORC1), one factor implicated in proper processing of phagocytosed material (32). The neurodegenerative phenotype in draper mutants may arise, at least in part, from incomplete clearance of neuronal corpses during development.…”