Gonçalves S, Patat J, Guida MC, Lachaussée N, Arrondel C, Helmstädter M, Boyer O, Gribouval O, Gubler MC, Mollet G, Rio M, Charbit M, Bole-Feysot C, Nitschke P, Huber TB, Wheeler PG, Haynes D, Juusola J, Billette de Villemeur T, Nava C, Afenjar A, Keren B, Bodmer R, Antignac C, Simons M. A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies. PLoS Genet. 2018 May 16;14(5):e1007386. PMID: 29768408.
The abstract: "Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-γ, with intellectual disability, microcephaly, cataracts and skeletal defects. In one of the families with additional cardiomyopathy and steroid-resistant nephrotic syndrome (SRNS), we found a homozygous variant in KAT2B, encoding the lysine acetyltransferase 2B, with impact on KAT2B protein levels in patient fibroblasts, suggesting that this second mutation might contribute to the increased disease spectrum. In order to define the contribution of ADD3 and KAT2B mutations for the patient phenotype, we performed functional experiments in the Drosophila model. We found that both mutations were unable to fully rescue the viability of the respective null mutants of the Drosophila homologs, hts and Gcn5, suggesting that they are indeed pathogenic in flies. While the KAT2B/Gcn5 mutation additionally showed a significantly reduced ability to rescue morphological and functional defects of cardiomyocytes and nephrocytes (podocyte-like cells), this was not the case for the ADD3 mutant rescue. Yet, the simultaneous knockdown of KAT2B and ADD3 synergistically impaired kidney and heart function in flies as well as the adhesion and migration capacity of cultured human podocytes, indicating that mutations in both genes may be required for the full clinical manifestation. Altogether, our studies describe the expansion of the phenotypic spectrum in ADD3 deficiency associated with a homozygous likely pathogenic KAT2B variant and thereby identify KAT2B as a susceptibility gene for kidney and heart disease in ADD3-associated disorders."
Thursday, May 17, 2018
Thursday, May 10, 2018
Review on how fly and worm studies are helping to elucidate mechanisms that how sleep is induced by sickness
Davis KC, Raizen DM. A mechanism for sickness sleep: lessons from invertebrates. J Physiol. 2017 Aug 15;595(16):5415-5424. PMID: 28028818; PubMed Central PMCID: PMC5556163.
From the abstract: "During health, animal sleep is regulated by an internal clock and by the duration of prior wakefulness. During sickness, sleep is regulated by cytokines released from either peripheral cells or from cells within the nervous system. These cytokines regulate central nervous system neurons to induce sleep. Recent research in the invertebrates Caenorhabditis elegans and Drosophila melanogaster has led to new insights into the mechanism of sleep during sickness. ... We will here review key findings that have elucidated the central neuroendocrine mechanism of sleep during sickness. ... We speculate that these mechanisms may play a maladaptive role in human pathological conditions such as in the fatigue and anorexia associated with autoimmune diseases, with major depression, and with unexplained chronic fatigue."
From the abstract: "During health, animal sleep is regulated by an internal clock and by the duration of prior wakefulness. During sickness, sleep is regulated by cytokines released from either peripheral cells or from cells within the nervous system. These cytokines regulate central nervous system neurons to induce sleep. Recent research in the invertebrates Caenorhabditis elegans and Drosophila melanogaster has led to new insights into the mechanism of sleep during sickness. ... We will here review key findings that have elucidated the central neuroendocrine mechanism of sleep during sickness. ... We speculate that these mechanisms may play a maladaptive role in human pathological conditions such as in the fatigue and anorexia associated with autoimmune diseases, with major depression, and with unexplained chronic fatigue."
Bubblegum and double bubble: silly fly gene names, serious study related to adrenoleukodystrophy
Gordon HB, Valdez L, Letsou A. Etiology and treatment of adrenoleukodystrophy: new insights from Drosophila. Dis Model Mech. 2018 May 8. pii: dmm.031286. PMID: 29739804.
From the abstract: "Adrenoleukodystrophy (ALD) is a fatal progressive neurodegenerative disorder affecting brain white matter. The most common form of ALD is X-linked (X-ALD) and results from mutation of the ABCD1-encoded very long chain fatty acid (VLCFA) transporter. X-ALD is clinically heterogeneous, with the cerebral form being the most severe. Diagnosed in boys usually between the ages of 4 and 8, cerebral X-ALD symptoms progress rapidly (in as little as two years) through declines in cognition, learning, and behavior, to paralysis and ultimately to a vegetative state and death. Currently, there are no good treatments for X-ALD. Here we exploit the Drosophila bubblegum (bgm) double bubble (dbb) model of neurometabolic disease to expand diagnostic power and therapeutic potential for adrenoleukodystrophy. We show that loss of the Drosophila long/very long chain acyl-CoA synthetase genes bgm and/or dbb is indistinguishable from loss of the Drosophila ABC transporter gene dABCD1 ... we show that it is a lack of lipid metabolic pathway product and not (as commonly thought) an accumulation of pathway precursor that is causative of neurometabolic disease: addition of medium chain fatty acids to the diet of bgm or dbb flies prevents the onset of neurodegeneration. Taken together, our data provide new foundations both for diagnosing adrenoleukodystrophy and for designing effective, mechanism-based treatment protocols."
From the abstract: "Adrenoleukodystrophy (ALD) is a fatal progressive neurodegenerative disorder affecting brain white matter. The most common form of ALD is X-linked (X-ALD) and results from mutation of the ABCD1-encoded very long chain fatty acid (VLCFA) transporter. X-ALD is clinically heterogeneous, with the cerebral form being the most severe. Diagnosed in boys usually between the ages of 4 and 8, cerebral X-ALD symptoms progress rapidly (in as little as two years) through declines in cognition, learning, and behavior, to paralysis and ultimately to a vegetative state and death. Currently, there are no good treatments for X-ALD. Here we exploit the Drosophila bubblegum (bgm) double bubble (dbb) model of neurometabolic disease to expand diagnostic power and therapeutic potential for adrenoleukodystrophy. We show that loss of the Drosophila long/very long chain acyl-CoA synthetase genes bgm and/or dbb is indistinguishable from loss of the Drosophila ABC transporter gene dABCD1 ... we show that it is a lack of lipid metabolic pathway product and not (as commonly thought) an accumulation of pathway precursor that is causative of neurometabolic disease: addition of medium chain fatty acids to the diet of bgm or dbb flies prevents the onset of neurodegeneration. Taken together, our data provide new foundations both for diagnosing adrenoleukodystrophy and for designing effective, mechanism-based treatment protocols."
Tuesday, May 8, 2018
FlyRNAi: Drosophila cell-based RNAi screen related to treat...
FlyRNAi: Drosophila cell-based RNAi screen related to treat...: Lin WH, He M, Fan YN, Baines RA. An RNAi-mediated screen identifies novel targets for next-generation antiepileptic drugs based on increased...
Characterization of a Drosophila model of NGLY1 deficiency
Defects in the Neuroendocrine Axis Contribute to Global Development Delay in a Drosophila Model of NGLY1 Deficiency
Tamy Portillo Rodriguez, Joshua D. Mast, Tom Hartl, Tom Lee, Peter Sand and Ethan O. Perlstein
G3: GENES, GENOMES, GENETICS Early online May 7, 2018; https://doi.org/10.1534/g3.118.300578
From the abstract: "N-glycanase 1 (NGLY1) Deficiency is a rare monogenic multi-system disorder ... Here we conducted a natural history study and chemical-modifier screen on the Drosophila melanogaster NGLY1 homolog, Pngl. We generated a new fly model of NGLY1 Deficiency, engineered with a nonsense mutation in Pngl at codon 420 that results in a truncation of the C-terminal carbohydrate-binding PAW domain. Homozygous mutant animals exhibit global development delay, pupal lethality and small body size as adults. ... We found that the cholesterol-derived ecdysteroid molting hormone 20-hydroxyecdysone (20E) partially rescued the global developmental delay in mutant homozygotes. Targeted expression of a human NGLY1 transgene to tissues involved in ecdysteroidogenesis, e.g., prothoracic gland, also partially rescues global developmental delay in mutant homozygotes. Finally, the proteasome inhibitor bortezomib is a potent enhancer of global developmental delay in our fly model ... Together, these results demonstrate the therapeutic relevance of a new fly model of NGLY1 Deficiency for drug discovery and gene modifier screens."
Tamy Portillo Rodriguez, Joshua D. Mast, Tom Hartl, Tom Lee, Peter Sand and Ethan O. Perlstein
G3: GENES, GENOMES, GENETICS Early online May 7, 2018; https://doi.org/10.1534/g3.118.300578
From the abstract: "N-glycanase 1 (NGLY1) Deficiency is a rare monogenic multi-system disorder ... Here we conducted a natural history study and chemical-modifier screen on the Drosophila melanogaster NGLY1 homolog, Pngl. We generated a new fly model of NGLY1 Deficiency, engineered with a nonsense mutation in Pngl at codon 420 that results in a truncation of the C-terminal carbohydrate-binding PAW domain. Homozygous mutant animals exhibit global development delay, pupal lethality and small body size as adults. ... We found that the cholesterol-derived ecdysteroid molting hormone 20-hydroxyecdysone (20E) partially rescued the global developmental delay in mutant homozygotes. Targeted expression of a human NGLY1 transgene to tissues involved in ecdysteroidogenesis, e.g., prothoracic gland, also partially rescues global developmental delay in mutant homozygotes. Finally, the proteasome inhibitor bortezomib is a potent enhancer of global developmental delay in our fly model ... Together, these results demonstrate the therapeutic relevance of a new fly model of NGLY1 Deficiency for drug discovery and gene modifier screens."
Monday, April 2, 2018
New fly model of mitochondrial disease associated with disruption of SLC25A46
1: Suda K, Ueoka I, Azuma Y, Muraoka Y, Yoshida H, Yamaguchi M. Novel Drosophila model for mitochondrial diseases by targeting of a solute carrier protein SLC25A46. Brain Res. 2018 Mar 28. pii: S0006-8993(18)30163-X. PMID: 29604258.
From the abstract: "Mutations in SLC25A46 gene have been identified in mitochondrial diseases that are sometimes classified as Charcot-Marie-Tooth disease type 2, optic atrophy and Leigh syndrome. Human SLC25A46 functions as a transporter across the outer mitochondrial membrane. However, it is still unknown how the neurodegeneration occurring in these diseases relates to the loss of SLC25A46 function. Drosophila has CG5755 (dSLC25A46) as a single human SLC25A46 homolog. Here we established pan-neuron specific dSLC25A46 knockdown flies, and examined their phenotypes. ... The dSLC25A46 knockdown fly ... recapitulates most of the phenotypes in mitochondrial disease patients, providing a useful tool to study these diseases."
From the abstract: "Mutations in SLC25A46 gene have been identified in mitochondrial diseases that are sometimes classified as Charcot-Marie-Tooth disease type 2, optic atrophy and Leigh syndrome. Human SLC25A46 functions as a transporter across the outer mitochondrial membrane. However, it is still unknown how the neurodegeneration occurring in these diseases relates to the loss of SLC25A46 function. Drosophila has CG5755 (dSLC25A46) as a single human SLC25A46 homolog. Here we established pan-neuron specific dSLC25A46 knockdown flies, and examined their phenotypes. ... The dSLC25A46 knockdown fly ... recapitulates most of the phenotypes in mitochondrial disease patients, providing a useful tool to study these diseases."
Drosophila analysis helps point to changes in the human gene VPS13D as the cause of a newly identified type of ataxia
Seong E, Insolera R, Dulovic M, Kamsteeg EJ, Trinh J, Brüggemann N, Sandford E, Li S, Ozel AB, Li JZ, Jewett T, Kievit AJA, Münchau A, Shakkottai V, Klein C, Collins C, Lohmann K, van de Warrenburg BP, Burmeister M. Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects. Ann Neurol. 2018 Mar 31. PMID: 29604224.
From the abstract: "... In an international collaboration, we independently performed exome sequencing in seven families with recessive ataxia and/or spastic paraplegia. To evaluate the role of VPS13D mutations, we evaluated a Drosophila knock-out model and investigated mitochondrial function in patient-derived fibroblast cultures. ... Our study demonstrates that compound heterozygous mutations in VPS13D cause movement disorders along the ataxia-spasticity spectrum, making VPS13D the fourth VPS13 paralog involved in neurological disorders. This article is protected by copyright. All rights reserved."
From the abstract: "... In an international collaboration, we independently performed exome sequencing in seven families with recessive ataxia and/or spastic paraplegia. To evaluate the role of VPS13D mutations, we evaluated a Drosophila knock-out model and investigated mitochondrial function in patient-derived fibroblast cultures. ... Our study demonstrates that compound heterozygous mutations in VPS13D cause movement disorders along the ataxia-spasticity spectrum, making VPS13D the fourth VPS13 paralog involved in neurological disorders. This article is protected by copyright. All rights reserved."
Subscribe to:
Posts (Atom)