Akiyama T, User SD, Gibson MC. Somatic clones heterozygous for recessive disease alleles of BMPR1A exhibit unexpected phenotypes in Drosophila. Elife. 2018 May 10;7. PMID: 29745898.
The abstract: "The majority of mutations studied in animal models are designated as recessive based on the absence of visible phenotypes in germline heterozygotes. Accordingly, genetic studies primarily rely on homozygous loss-of-function to determine gene requirements, and a conceptually-related 'two-hit model' remains the central paradigm in cancer genetics. Here we investigate pathogenesis due to somatic mutation in epithelial tissues, a process that predominantly generates heterozygous cell clones. To study somatic mutation in Drosophila, we generated inducible alleles that mimic human Juvenile polyposis-associated BMPR1A mutations. Unexpectedly, four of these mutations had no phenotype in heterozygous carriers but exhibited clear tissue-level effects when present in somatic clones of heterozygous cells. We conclude that these alleles are indeed recessive when present in the germline, but nevertheless deleterious when present in heterozygous clones. This unforeseen effect, deleteriousheteromosaicism, suggests a 'one-hit' mechanism for disease initiation that may explain some instances of pathogenesis associated with spontaneous mutation."
Thursday, May 17, 2018
Review of Drosophila research related to ALS
Zhang K, Coyne AN, Lloyd TE. Drosophila models of amyotrophic lateral sclerosis with defects in RNA metabolism. Brain Res. 2018 May 9. PMID: 29752901.
From the abstract: " ... The conservation of nervous system biology coupled with the rapid life cycle and powerful genetic tools in the fly have enabled the identification of novel therapeutic targets that have been validated in vertebrate model systems and human patients. A recent example is in the study of the devastating motor neuron degenerative disease amyotrophic lateral sclerosis (ALS). ... In this review, we will discuss the utilization of Drosophila models of ALS with defects in RNA metabolism."
From the abstract: " ... The conservation of nervous system biology coupled with the rapid life cycle and powerful genetic tools in the fly have enabled the identification of novel therapeutic targets that have been validated in vertebrate model systems and human patients. A recent example is in the study of the devastating motor neuron degenerative disease amyotrophic lateral sclerosis (ALS). ... In this review, we will discuss the utilization of Drosophila models of ALS with defects in RNA metabolism."
Study of a fly model of fragile X-syndrome suggests "a potentially general mechanism for intellectual disability"
Franco LM, Okray Z, Linneweber GA, Hassan BA, Yaksi E. Reduced Lateral Inhibition Impairs Olfactory Computations and Behaviors in a Drosophila Model of Fragile X Syndrome. Curr Biol. 2017 Apr 24;27(8):1111-1123. PMID: 28366741; PMCID: PMC5405172.
From the abstract: "Fragile X syndrome (FXS) patients present neuronal alterations that lead to severe intellectual disability, but the underlying neuronal circuit mechanisms are poorly understood. An emerging hypothesis postulates that reduced GABAergic inhibition of excitatory neurons is a key component in the pathophysiology of FXS. Here, we directly test this idea in a FXS Drosophila model. ... We provide direct evidence that deficient inhibition impairs sensory computations and behavior in an in vivo model of FXS. Together with evidence of impaired inhibition in autism and Rett syndrome, these findings suggest a potentially general mechanism for intellectual disability."
Also appearing recently, this review:
Drozd M, Bardoni B, Capovilla M. Modeling Fragile X Syndrome in Drosophila. Front Mol Neurosci. 2018 Apr 16;11:124. doi: 10.3389/fnmol.2018.00124. PMID: 29713264; PMCID: PMC5911982.
From the abstract: "Fragile X syndrome (FXS) patients present neuronal alterations that lead to severe intellectual disability, but the underlying neuronal circuit mechanisms are poorly understood. An emerging hypothesis postulates that reduced GABAergic inhibition of excitatory neurons is a key component in the pathophysiology of FXS. Here, we directly test this idea in a FXS Drosophila model. ... We provide direct evidence that deficient inhibition impairs sensory computations and behavior in an in vivo model of FXS. Together with evidence of impaired inhibition in autism and Rett syndrome, these findings suggest a potentially general mechanism for intellectual disability."
Also appearing recently, this review:
Drozd M, Bardoni B, Capovilla M. Modeling Fragile X Syndrome in Drosophila. Front Mol Neurosci. 2018 Apr 16;11:124. doi: 10.3389/fnmol.2018.00124. PMID: 29713264; PMCID: PMC5911982.
Fly studies help shed light on contribution of KAT2B variants to ADD3-associated disorders
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."
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 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...
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