Leigh Syndrome in Drosophila melanogaster

Da‐Ré, Caterina; Stockum, Sophia von; Biscontin, Alberto; Millino, Caterina; Cisotto, Paola; Zordan, Mauro Agostino; Zeviani, Massimo; Bernardi, Paolo; Pittà, Cristiano De; Costa, Rodolfo

doi:10.1074/jbc.m114.602938

Cited by 23 publications

(12 citation statements)

References 61 publications

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“…, those linked to the neuron- and muscle-specific elav and Mhc promoters, respectively ( Osterwalder et al 2001 ), or for specific expression in other tissues such as the fat body ( Roman et al 2001 ). Subsequently, the “ubiquitous” GS drivers (such as tubGS and Actin5C-GS ) have been brought into use for inducing broad expression, both in adults and larvae ( Ford et al 2007 ; Waskar et al 2009 ; Wigby et al 2011 ; Paik et al 2012 ; Kuo et al 2012 ; Kemppainen et al 2014a , b ; Sun et al 2014 ; Da-Rè et al 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Ligand-Bound GeneSwitch Causes Developmental Aberrations inDrosophilathat Are Alleviated by the Alternative Oxidase

Andjelković

Kemppainen

Jacobs

2016

G3 Genes|Genomes|Genetics

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Culture of Drosophila expressing the steroid-dependent GeneSwitch transcriptional activator under the control of the ubiquitous α-tubulin promoter was found to produce extensive pupal lethality, as well as a range of dysmorphic adult phenotypes, in the presence of high concentrations of the inducing drug RU486. Prominent among these was cleft thorax, seen previously in flies bearing mutant alleles of the nuclear receptor Ultraspiracle and many other mutants, as well as notched wings, leg malformations, and bristle abnormalities. Neither the α-tubulin-GeneSwitch driver nor the inducing drug on their own produced any of these effects. A second GeneSwitch driver, under the control of the daughterless promoter, which gave much lower and more tissue-restricted transgene expression, exhibited only mild bristle abnormalities in the presence of high levels of RU486. Coexpression of the alternative oxidase (AOX) from Ciona intestinalis produced a substantial shift in the developmental outcome toward a wild-type phenotype, which was dependent on the AOX expression level. Neither an enzymatically inactivated variant of AOX, nor GFP, or the alternative NADH dehydrogenase Ndi1 from yeast gave any such rescue. Users of the GeneSwitch system should be aware of the potential confounding effects of its application in developmental studies.

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Section: Discussionmentioning

confidence: 99%

Ligand-Bound GeneSwitch Causes Developmental Aberrations inDrosophilathat Are Alleviated by the Alternative Oxidase

Andjelković

Kemppainen

Jacobs

2016

G3 Genes|Genomes|Genetics

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“…Based on additional genetic and biochemical data, Zhang et al, concluded that Sicily acts as a co-chaperone for Hsp90 to stabilize Complex I proteins prior to their entry into the mitochondria. Together with insights obtained from other fly genes whose human orthologs are also linked to Leigh syndrome such as ND-42 (Burman et al, 2014) and Surf1 (human ortholog: SURF1, Da-Rè et al, 2014), we now have a better understanding of this disorder at the molecular, cellular and organismal level.…”

Section: Mitochondrial Dysfunction Oxidative Stress and Lipid Droplementioning

confidence: 99%

Unraveling Novel Mechanisms of Neurodegeneration Through a Large-Scale Forward Genetic Screen in Drosophila

Deal

Yamamoto

2019

Front. Genet.

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Neurodegeneration is characterized by progressive loss of neurons. Genetic and environmental factors both contribute to demise of neurons, leading to diverse devastating cognitive and motor disorders, including Alzheimer’s and Parkinson’s diseases in humans. Over the past few decades, the fruit fly, Drosophila melanogaster, has become an integral tool to understand the molecular, cellular and genetic mechanisms underlying neurodegeneration. Extensive tools and sophisticated technologies allow Drosophila geneticists to identify and study evolutionarily conserved genes that are essential for neural maintenance. In this review, we will focus on a large-scale mosaic forward genetic screen on the fly X-chromosome that led to the identification of a number of essential genes that exhibit neurodegenerative phenotypes when mutated. Most genes identified from this screen are evolutionarily conserved and many have been linked to human diseases with neurological presentations. Systematic electrophysiological and ultrastructural characterization of mutant tissue in the context of the Drosophila visual system, followed by a series of experiments to understand the mechanism of neurodegeneration in each mutant led to the discovery of novel molecular pathways that are required for neuronal integrity. Defects in mitochondrial function, lipid and iron metabolism, protein trafficking and autophagy are recurrent themes, suggesting that insults that eventually lead to neurodegeneration may converge on a set of evolutionarily conserved cellular processes. Insights from these studies have contributed to our understanding of known neurodegenerative diseases such as Leigh syndrome and Friedreich’s ataxia and have also led to the identification of new human diseases. By discovering new genes required for neural maintenance in flies and working with clinicians to identify patients with deleterious variants in the orthologous human genes, Drosophila biologists can play an active role in personalized medicine.

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“…In a LS Drosophila model, the constitutive SURF1 knockdown is lethal in larvae that however display defects in all complexes of the mitochondrial respiratory chain (MRC) and impaired muscular development. In a conditional central nervous system (CNS)-restricted Drosophila model the knockdown of SURF1 leads to isolated COX deficiency in adult flies [ 17 ]. The failure of small animal models, in particular rodents, to mimic the main features of the human syndrome prompted us to generate a large animal model [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

SURF1 knockout cloned pigs: Early onset of a severe lethal phenotype

Quadalti

Brunetti

Lagutina

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Leigh syndrome (LS) associated with cytochrome c oxidase (COX) deficiency is an early onset, fatal mitochondrial encephalopathy, leading to multiple neurological failure and eventually death, usually in the first decade of life. Mutations in SURF1, a nuclear gene encoding a mitochondrial protein involved in COX assembly, are among the most common causes of LS. LSSURF1 patients display severe, isolated COX deficiency in all tissues, including cultured fibroblasts and skeletal muscle. Recombinant, constitutive SURF1−/− mice show diffuse COX deficiency, but fail to recapitulate the severity of the human clinical phenotype. Pigs are an attractive alternative model for human diseases, because of their size, as well as metabolic, physiological and genetic similarity to humans. Here, we determined the complete sequence of the swine SURF1 gene, disrupted it in pig primary fibroblast cell lines using both TALENs and CRISPR/Cas9 genome editing systems, before finally generating SURF1−/− and SURF1−/+ pigs by Somatic Cell Nuclear Transfer (SCNT). SURF1−/− pigs were characterized by failure to thrive, muscle weakness and highly reduced life span with elevated perinatal mortality, compared to heterozygous SURF1−/+ and wild type littermates. Surprisingly, no obvious COX deficiency was detected in SURF1−/− tissues, although histochemical analysis revealed the presence of COX deficiency in jejunum villi and total mRNA sequencing (RNAseq) showed that several COX subunit-encoding genes were significantly down-regulated in SURF1−/− skeletal muscles. In addition, neuropathological findings, indicated a delay in central nervous system development of newborn SURF1−/− piglets. Our results suggest a broader role of sSURF1 in mitochondrial bioenergetics.

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Leigh Syndrome in Drosophila melanogaster

Cited by 23 publications

References 61 publications

Ligand-Bound GeneSwitch Causes Developmental Aberrations inDrosophilathat Are Alleviated by the Alternative Oxidase

Ligand-Bound GeneSwitch Causes Developmental Aberrations inDrosophilathat Are Alleviated by the Alternative Oxidase

Unraveling Novel Mechanisms of Neurodegeneration Through a Large-Scale Forward Genetic Screen in Drosophila

SURF1 knockout cloned pigs: Early onset of a severe lethal phenotype

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