López Del Amo V, Seco-Cervera M, García-Giménez JL, Whitworth AJ, Pallardó FV, Galindo MI. Mitochondrial defects and neuromuscular degeneration caused by altered expression of Drosophila Gdap1: implications for the Charcot-Marie-Tooth neuropathy. Hum Mol Genet. 2015 Jan 1;24(1):21-36. PMID: 25122658.
From the abstract: "One of the genes involved in Charcot-Marie-Tooth (CMT) disease, an inherited peripheral neuropathy, is GDAP1. In this work, we show that there is a true ortholog of this gene in Drosophila, which we have named Gdap1. By up- and down-regulation of Gdap1 in a tissue-specific manner, we show that altering its levels of expression produces changes in mitochondrial size, morphology and distribution, and neuronal and muscular degeneration. ... Our results contribute to a better understanding of the role of mitochondria in CMT disease and pave the way to generate clinically relevant disease models to study the relationship between mitochondrial dynamics and peripheral neurodegeneration."
Wednesday, October 26, 2016
Can we outrun aging? Fly study of impact of fatiguing exercise on aging
Zheng L, Feng Y, Wen DT, Wang H, Wu XS. Fatiguing exercise initiated later in life reduces incidence of fibrillation and improves sleep quality in Drosophila. Age (Dordr). 2015 Aug;37(4):9816. PMID: 26206392; PMCID: PMC4512962.
From the abstract: "As the human body ages, the risk of heart disease and stroke greatly increases. While there is evidence that lifelong exercise is beneficial to the heart's health, the effects of beginning exercise later in life remain unclear. This study aimed to investigate whether exercise training started later in life is beneficial to cardiac aging in Drosophila. ... We found that 2.0 and 2.5 h of exercise caused exercise-induced fatigue, and fatiguing exercise is beneficial for cardiac and healthy aging overall. This study provides a basis for further study in humans on the impact of beginning an exercise regimen later in life on cardiac health."
From the abstract: "As the human body ages, the risk of heart disease and stroke greatly increases. While there is evidence that lifelong exercise is beneficial to the heart's health, the effects of beginning exercise later in life remain unclear. This study aimed to investigate whether exercise training started later in life is beneficial to cardiac aging in Drosophila. ... We found that 2.0 and 2.5 h of exercise caused exercise-induced fatigue, and fatiguing exercise is beneficial for cardiac and healthy aging overall. This study provides a basis for further study in humans on the impact of beginning an exercise regimen later in life on cardiac health."
Fly studies contribute to study focused on centronuclear myopathy
Chin YH, Lee A, Kan HW, Laiman J, Chuang MC, Hsieh ST, Liu YW. Dynamin-2 mutations associated with centronuclear myopathy are hypermorphic and lead to T-tubule fragmentation. Hum Mol Genet. 2015 Oct 1;24(19):5542-54. PMID: 26199319.
From the abstract: "Skeletal muscle requires adequate membrane trafficking and remodeling to maintain its normal structure and functions. Consequently, many human myopathies are caused by mutations in membrane trafficking machinery. The large GTPase dynamin-2 (Dyn2) is best known for catalyzing membrane fission during clathrin-mediated endocytosis (CME), which is critical for cell signaling and survival. Despite its ubiquitous expression, mutations of Dyn2 are associated with two tissue-specific congenital disorders: centronuclear myopathy (CNM) and Charcot-Marie-Tooth (CMT) neuropathy. Several disease models for CNM-Dyn2 have been established ... . ... we found that the expression of CNM-Dyn2 mutants does not impair CME in myoblast, but leads to T-tubule fragmentation in both C2C12-derived myotubes and Drosophila body wall muscle. Our results demonstrate that CNM-Dyn2 mutants are gain-of-function mutations, and their primary effect in muscle is T-tubule disorganization, which explains the susceptibility of muscle to Dyn2 hyperactivity."
From the abstract: "Skeletal muscle requires adequate membrane trafficking and remodeling to maintain its normal structure and functions. Consequently, many human myopathies are caused by mutations in membrane trafficking machinery. The large GTPase dynamin-2 (Dyn2) is best known for catalyzing membrane fission during clathrin-mediated endocytosis (CME), which is critical for cell signaling and survival. Despite its ubiquitous expression, mutations of Dyn2 are associated with two tissue-specific congenital disorders: centronuclear myopathy (CNM) and Charcot-Marie-Tooth (CMT) neuropathy. Several disease models for CNM-Dyn2 have been established ... . ... we found that the expression of CNM-Dyn2 mutants does not impair CME in myoblast, but leads to T-tubule fragmentation in both C2C12-derived myotubes and Drosophila body wall muscle. Our results demonstrate that CNM-Dyn2 mutants are gain-of-function mutations, and their primary effect in muscle is T-tubule disorganization, which explains the susceptibility of muscle to Dyn2 hyperactivity."
Drosophila studies contribute to research on possible links between the metal copper and schizophrenia
Gokhale A, Vrailas-Mortimer A, Larimore J, Comstra HS, Zlatic SA, Werner E, Manvich DF, Iuvone PM, Weinshenker D, Faundez V. Neuronal copper homeostasis susceptibility by genetic defects in dysbindin, a schizophrenia susceptibility factor. Hum Mol Genet. 2015 Oct 1;24(19):5512-23. PMID: 26199316; PMCID: PMC4572075.
From the abstract: "Environmental factors and susceptible genomes interact to determine the risk of neurodevelopmental disorders. ... Here we focus on the schizophrenia susceptibility gene DTNBP1 and its product dysbindin, a subunit of the BLOC-1 complex, and describe a neuronal pathway modulating copper metabolism via ATP7A. ... Dysbindin/BLOC-1 loss-of-function alleles do not affect cell and tissue copper content, yet they alter the susceptibility to toxic copper challenges in both mammalian cells and Drosophila. Our results demonstrate that perturbations downstream of the schizophrenia susceptibility gene DTNBP1 confer susceptibility to copper, a metal that in excess is a neurotoxin and whose depletion constitutes a micronutrient deficiency."
From the abstract: "Environmental factors and susceptible genomes interact to determine the risk of neurodevelopmental disorders. ... Here we focus on the schizophrenia susceptibility gene DTNBP1 and its product dysbindin, a subunit of the BLOC-1 complex, and describe a neuronal pathway modulating copper metabolism via ATP7A. ... Dysbindin/BLOC-1 loss-of-function alleles do not affect cell and tissue copper content, yet they alter the susceptibility to toxic copper challenges in both mammalian cells and Drosophila. Our results demonstrate that perturbations downstream of the schizophrenia susceptibility gene DTNBP1 confer susceptibility to copper, a metal that in excess is a neurotoxin and whose depletion constitutes a micronutrient deficiency."
Modeling neurodegenerative disease
Lepesant JA. The promises of neurodegenerative disease modeling. C R Biol. 2015 Aug-Sep;338(8-9):584-92. PMID: 26210484.
From the abstract: "The rise in the prevalence of neurodegenerative diseases parallels the rapid increase in human lifespan. Despite intensive research, the molecular and cellular mechanisms underlying the onset and progression of these devastating diseases with age are still poorly understood. ... This review will focus on the advantages offered by the genetic tools available in Drosophila for combining powerful strategies in order to tackle the causative factors of these complex pathologies and help to elaborate efficient drugs to treat them."
From the abstract: "The rise in the prevalence of neurodegenerative diseases parallels the rapid increase in human lifespan. Despite intensive research, the molecular and cellular mechanisms underlying the onset and progression of these devastating diseases with age are still poorly understood. ... This review will focus on the advantages offered by the genetic tools available in Drosophila for combining powerful strategies in order to tackle the causative factors of these complex pathologies and help to elaborate efficient drugs to treat them."
Thursday, October 6, 2016
Preprint describes new fly model of Saposin deficiency
A Saposin deficiency model in Drosophila: lysosomal storage, progressive neurodegeneration, sensory physiological decline and defective calcium homeostasis
J Hindle, Sarita Hebbar, Dominik Schwudke, Christopher J Elliott, Sean T Sweeney
doi: http://dx.doi.org/10.1101/078725
From the abstract: "Saposin deficiency is a childhood neurodegenerative lysosomal storage disorder (LSD) that can cause premature death within three months of life. Saposins are activator proteins that promote the function of lysosomal hydrolases in the degradation of sphingolipids. There are four saposin proteins in humans, which are encoded by the prosaposin gene. Mutations causing an absence of individual saposins or the whole prosaposin gene lead to distinct LSDs due to the storage of different classes of sphingolipids. The pathological events leading to neuronal dysfunction induced by lysosomal storage of sphingolipids are as yet poorly defined. We have generated and characterised a Drosophila model of saposin deficiency that shows striking similarities to the human diseases. ..."
J Hindle, Sarita Hebbar, Dominik Schwudke, Christopher J Elliott, Sean T Sweeney
doi: http://dx.doi.org/10.1101/078725
From the abstract: "Saposin deficiency is a childhood neurodegenerative lysosomal storage disorder (LSD) that can cause premature death within three months of life. Saposins are activator proteins that promote the function of lysosomal hydrolases in the degradation of sphingolipids. There are four saposin proteins in humans, which are encoded by the prosaposin gene. Mutations causing an absence of individual saposins or the whole prosaposin gene lead to distinct LSDs due to the storage of different classes of sphingolipids. The pathological events leading to neuronal dysfunction induced by lysosomal storage of sphingolipids are as yet poorly defined. We have generated and characterised a Drosophila model of saposin deficiency that shows striking similarities to the human diseases. ..."
Thursday, September 15, 2016
Fly study points to importance and approaches for precision/personalized medicine in Ret fusion-associated cancers
Levinson S, Cagan RL. Drosophila Cancer Models Identify Functional Differences between Ret Fusions. Cell Rep. 2016 Sep 13;16(11):3052-3061. PMID: 27626672.
Abstract: "We generated and compared Drosophila models of RET fusions CCDC6-RET and NCOA4-RET. Both RET fusions directed cells to migrate, delaminate, and undergo EMT, and both resulted in lethality when broadly expressed. In all phenotypes examined, NCOA4-RET was more severe than CCDC6-RET, mirroring their effects on patients. A functional screen against the Drosophila kinome and a library of cancer drugs found that CCDC6-RET and NCOA4-RET acted through different signaling networks and displayed distinct drug sensitivities. Combining data from the kinome and drug screens identified the WEE1 inhibitor AZD1775 plus the multi-kinase inhibitor sorafenib as a synergistic drug combination that is specific for NCOA4-RET. Our work emphasizes the importance of identifying and tailoring a patient's treatment to their specific RET fusion isoform and identifies a multi-targeted therapy that may prove effective against tumors containing the NCOA4-RET fusion."
Abstract: "We generated and compared Drosophila models of RET fusions CCDC6-RET and NCOA4-RET. Both RET fusions directed cells to migrate, delaminate, and undergo EMT, and both resulted in lethality when broadly expressed. In all phenotypes examined, NCOA4-RET was more severe than CCDC6-RET, mirroring their effects on patients. A functional screen against the Drosophila kinome and a library of cancer drugs found that CCDC6-RET and NCOA4-RET acted through different signaling networks and displayed distinct drug sensitivities. Combining data from the kinome and drug screens identified the WEE1 inhibitor AZD1775 plus the multi-kinase inhibitor sorafenib as a synergistic drug combination that is specific for NCOA4-RET. Our work emphasizes the importance of identifying and tailoring a patient's treatment to their specific RET fusion isoform and identifies a multi-targeted therapy that may prove effective against tumors containing the NCOA4-RET fusion."
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