Developmentally regulated autophagy is required for eye formation in
            <i>Drosophila</i>

Billes, Viktor; Kovács, Tibor; Manzéger, Anna; Lőrincz, Péter; Szincsák, Sára; Regős, Ágnes; Kulcsár, Péter István; Korcsmáros, Tamás; Lukácsovich, Tamás; Hoffmann, Gyula; Erdélyi, Miklós; Mihály, József; Takács‐Vellai, Krisztina; Sass, Miklós; Vellai, Tibor

doi:10.1080/15548627.2018.1454569

Cited by 21 publications

(17 citation statements)

References 101 publications

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“…These findings demonstrate that unbalanced autophagy turnover is responsible for retinal damage and functional alterations caused by defective full-length dystrophin. Previous reports in D. melanogaster suggest that cell death-suppressing and differentiating effects of autophagy are required for eye formation [ 86 ]. In addition, defects in the autophagic pathway of Drosophila photoreceptors are shown at the basis of retinal degeneration [ 87 ].…”

Section: Discussionmentioning

confidence: 99%

Defects of full-length dystrophin trigger retinal neuron damage and synapse alterations by disrupting functional autophagy

Catalani

Bongiorni

Taddei

et al. 2020

Cell. Mol. Life Sci.

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Dystrophin (dys) mutations predispose Duchenne muscular disease (DMD) patients to brain and retinal complications. Although different dys variants, including long dys products, are expressed in the retina, their function is largely unknown. We investigated the putative role of full-length dystrophin in the homeostasis of neuro-retina and its impact on synapsis stabilization and cell fate. Retinas of mdx mice, the most used DMD model which does not express the 427-KDa dys protein (Dp427), showed overlapped cell death and impaired autophagy. Apoptotic neurons in the outer plexiform/inner nuclear layer and the ganglion cell layer had an impaired autophagy with accumulated autophagosomes. The autophagy dysfunction localized at photoreceptor axonal terminals and bipolar, amacrine, and ganglion cells. The absence of Dp427 does not cause a severe phenotype but alters the neuronal architecture, compromising mainly the pre-synaptic photoreceptor terminals and their post-synaptic sites. The analysis of two dystrophic mutants of the fruit fly Drosophila melanogaster, the homozygous Dys E17 and Dys EP3397 , lacking functional large-isoforms of dystrophin-like protein, revealed rhabdomere degeneration. Structural damages were evident in the internal network of retina/lamina where photoreceptors make the first synapse. Both accumulated autophagosomes and apoptotic features were detected and the visual system was functionally impaired. The reactivation of the autophagosome turnover by rapamycin prevented neuronal cell death and structural changes of mutant flies and, of interest, sustained autophagy ameliorated their response to light. Overall, these findings indicate that functional full-length dystrophin is required for synapsis stabilization and neuronal survival of the retina, allowing also proper autophagy as a prerequisite for physiological cell fate and visual properties.

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Section: Discussionmentioning

confidence: 99%

Defects of full-length dystrophin trigger retinal neuron damage and synapse alterations by disrupting functional autophagy

Catalani

Bongiorni

Taddei

et al. 2020

Cell. Mol. Life Sci.

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“…Accordingly, typical hallmarks of neuroretina degeneration, for instance, vacuoles and damaged mitochondria, were not detectable at the ultrastructural level in eye neurons. Cell death-suppressing and differentiating effects of autophagy are required for Drosophila eye formation [ 51 ]. Also, defects in the autophagic pathway of Drosophila photoreceptors were involved in retinal degeneration [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Nutraceutical Strategy to Counteract Eye Neurodegeneration and Oxidative Stress in Drosophila melanogaster Fed with High-Sugar Diet

et al. 2021

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Aberrant production of reactive oxygen species (ROS) is a common feature of damaged retinal neurons in diabetic retinopathy, and antioxidants may exert both preventive and therapeutic action. To evaluate the beneficial and antioxidant properties of food supplementation with Lisosan G, a powder of bran and germ of grain (Triticum aestivum) obtained by fermentation with selected lactobacillus and natural yeast strains, we used an in vivo model of hyperglycemia-induced retinal damage, the fruit fly Drosophila melanogaster fed with high-sucrose diet. Lisosan G positively affected the visual system of hyperglycemic flies at structural/functional level, decreased apoptosis, and reactivated protective autophagy at the retina internal network. Also, in high sucrose-fed Drosophila, Lisosan G reduced the levels of brain ROS and retina peroxynitrite. The analysis of oxidative stress-related metabolites suggested 7,8-dihydrofolate, uric acid, dihydroorotate, γ-L-glutamyl-L-cysteine, allantoin, cysteinyl-glycine, and quinolate as key mediators of Lisosan G-induced inhibition of neuronal ROS, along with the upregulation of glutathione system. Of note, Lisosan G may impact oxidative stress and the ensuing retinal cell death, also independently from autophagy, although the autophagy-ROS cross-talk is critical. This study demonstrated that the continuous supplementation with the alimentary integrator Lisosan G exerts a robust and multifaceted antioxidant effect on retinal neurons, thus providing efficacious neuroprotection of hyperglycemic eye.

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“…RNAi lines against the following genes are from the TRiP collection at Harvard Medical School and were obtained from the BDSC: egfp (#41556); dredd (#34070); 85 dnaseII (#63635)*; dor (#44426)*; car (#34007); 86 parp1 (#57265); 87 cathB (#33953); 88 cathL (#41939); 89 atm (#44417)*; chk2 (#64482); 90 atr (#41934); 90 chk1 (#36685); 90 atg7 (#34369); 91 atg6 (#35741); 91 atg5 (#34899); 92 atg8a (#34340); 92 duox (#32903); 93 orc2 (#43215)*; cyp1 Ri1 (#33950); 94 cyp1 Ri2 (#33001)*; CG17266 (#58350)*; CG2852 (#55196)*.…”

Section: Methodsmentioning

confidence: 99%

DNase II mediates a parthanatos-like developmental cell death pathway in Drosophila primordial germ cells

et al. 2021

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During Drosophila embryonic development, cell death eliminates 30% of the primordial germ cells (PGCs). Inhibiting apoptosis does not prevent PGC death, suggesting a divergence from the conventional apoptotic program. Here, we demonstrate that PGCs normally activate an intrinsic alternative cell death (ACD) pathway mediated by DNase II release from lysosomes, leading to nuclear translocation and subsequent DNA double-strand breaks (DSBs). DSBs activate the DNA damage-sensing enzyme, Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) and the ATR/Chk1 branch of the DNA damage response. PARP-1 and DNase II engage in a positive feedback amplification loop mediated by the release of PAR polymers from the nucleus and the nuclear accumulation of DNase II in an AIF- and CypA-dependent manner, ultimately resulting in PGC death. Given the anatomical and molecular similarities with an ACD pathway called parthanatos, these findings reveal a parthanatos-like cell death pathway active during Drosophila development.

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Developmentally regulated autophagy is required for eye formation in Drosophila

Abstract: A c c e p t e d M a n u s c r i p t Billes et al., 2018., Revision 3 Autophagy in eye development 3 microtubule-associated protein 1 light chain 3; MF, morphogenetic furrow; PE, Tables (S1, S2), and Suppl. Figures and Figure Legends (S1 to S31).A c c e p t e d M a n u s c r i p t

Cited by 21 publications

References 101 publications

Defects of full-length dystrophin trigger retinal neuron damage and synapse alterations by disrupting functional autophagy

Defects of full-length dystrophin trigger retinal neuron damage and synapse alterations by disrupting functional autophagy

Nutraceutical Strategy to Counteract Eye Neurodegeneration and Oxidative Stress in Drosophila melanogaster Fed with High-Sugar Diet

DNase II mediates a parthanatos-like developmental cell death pathway in Drosophila primordial germ cells

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