Barardo D, Thornton D, Thoppil H, Walsh M, Sharifi S, Ferreira S, Anžič A, Fernandes M, Monteiro P, Grum T, Cordeiro R, De-Souza EA, Budovsky A, Araujo N, Gruber J, Petrascheck M, Fraifeld VE, Zhavoronkov A, Moskalev A, de Magalhães JP. The DrugAge database of aging-related drugs. Aging Cell. 2017 Jun;16(3):594-597. PMID: 28299908; PMCID: PMC5418190.
From the abstract: "Aging is a major worldwide medical challenge. Not surprisingly, identifying drugs and compounds that extend lifespan in model organisms is a growing research area. Here, we present DrugAge (http://genomics.senescence.info/drugs/), a curated database of lifespan-extending drugs and compounds. At the time of writing, DrugAge contains 1316 entries featuring 418 different compounds from studies across 27 model organisms, including worms, flies, yeast and mice. Data were manually curated from 324 publications. ... DrugAge is freely available online for the scientific community and will be an important resource for biogerontologists."
Monday, December 11, 2017
Diet-based Drosophila model of kidney stones
Chung VY, Turney BW. A Drosophila genetic model of nephrolithiasis: transcriptional changes in response to diet induced stone formation. BMC Urol. 2017 Nov 28;17(1):109. PMID: 29183349; PMCID: PMC5706311.
From the abstract: "... We have used Drosophila as a genetic model to study the transcriptional response to stone formation secondary to dietary manipulation. ... Wild-type male flies were raised on standard medium supplemented with lithogenic agents: control, sodium oxalate (NaOx) and ethylene glycol (EG). ... Crystal formation was visualized in 20%(±2.2) of flies on control diet, 73%(±3.6) on NaOx diet and 84%(±2.2) on EG diet. ... Fifty-eight genes were differentially expressed (FDR <0.05, p < 0.05) in NaOx diet and 20 genes in EG diet. ... This genetic model could be potentially used to identify the candidate genes that influence stone risk hence providing more insight to the pathogenesis of human stone disease."
From the abstract: "... We have used Drosophila as a genetic model to study the transcriptional response to stone formation secondary to dietary manipulation. ... Wild-type male flies were raised on standard medium supplemented with lithogenic agents: control, sodium oxalate (NaOx) and ethylene glycol (EG). ... Crystal formation was visualized in 20%(±2.2) of flies on control diet, 73%(±3.6) on NaOx diet and 84%(±2.2) on EG diet. ... Fifty-eight genes were differentially expressed (FDR <0.05, p < 0.05) in NaOx diet and 20 genes in EG diet. ... This genetic model could be potentially used to identify the candidate genes that influence stone risk hence providing more insight to the pathogenesis of human stone disease."
Study using a Drosophila model of traumatic brain injury suggests link to mitochondrial activity
Sen A, Gurdziel K, Liu J, Qu W, Nuga OO, Burl RB, Hüttemann M, Pique-Regi R, Ruden DM. Smooth, an hnRNP-L Homolog, Might Decrease Mitochondrial Metabolism by Post-Transcriptional Regulation of Isocitrate Dehydrogenase (Idh) and Other Metabolic Genes in the Sub-Acute Phase of Traumatic Brain Injury. Front Genet. 2017 Nov 15;8:175. PMID: 29187863; PMCID: PMC5694756.
From the abstract: "Traumatic brain injury (TBI) can cause persistent pathological alteration of neurons. ... To investigate the underlying genetic and molecular basis of TBI, we subjected w1118 Drosophila melanogaster to mild closed head trauma and found that mitochondrial activity is reduced in the brains of these flies 24 h after inflicting trauma. To determine the transcriptomic changes after mild TBI, we collected fly heads 24 h after inflicting trauma, and performed RNA-seq analyses. ... Based on these results, we propose a model in which TBI temporarily decreases mitochondrial activity in the brain 24 h after inflicting trauma ... We further propose that decreasing metabolism after TBI in such a manner is a protective mechanism that gives the brain time to repair cellular damage induced by TBI."
From the abstract: "Traumatic brain injury (TBI) can cause persistent pathological alteration of neurons. ... To investigate the underlying genetic and molecular basis of TBI, we subjected w1118 Drosophila melanogaster to mild closed head trauma and found that mitochondrial activity is reduced in the brains of these flies 24 h after inflicting trauma. To determine the transcriptomic changes after mild TBI, we collected fly heads 24 h after inflicting trauma, and performed RNA-seq analyses. ... Based on these results, we propose a model in which TBI temporarily decreases mitochondrial activity in the brain 24 h after inflicting trauma ... We further propose that decreasing metabolism after TBI in such a manner is a protective mechanism that gives the brain time to repair cellular damage induced by TBI."
Friday, December 8, 2017
"Proboscus extension response" developed in fly study relevant to Parkinsons disease
Cording AC, Shiaelis N, Petridi S, Middleton CA, Wilson LG, Elliott CJH. Targeted kinase inhibition relieves slowness and tremor in a Drosophila model of LRRK2 Parkinson's disease. NPJ Parkinsons Dis. 2017 Dec 4;3:34. PMID: 29214211; PMCID: PMC5715132.
From the abstract: "In a number of Drosophila models of genetic Parkinson's disease (PD) flies climb more slowly than wild-type controls. However, this assay does not distinguish effects of PD-related genes on gravity sensation, "arousal", central pattern generation of leg movements, or muscle. To address this problem, we have developed an assay for the fly proboscis extension response (PER). This is attractive because the PER has a simple, well-identified reflex neural circuit ... We conclude the Drosophila PER provides an excellent model of LRRK2 motor deficits showing bradykinesia, akinesia, hypokinesia, and increased tremor, with the possibility to localize changes in neural signaling."
From the abstract: "In a number of Drosophila models of genetic Parkinson's disease (PD) flies climb more slowly than wild-type controls. However, this assay does not distinguish effects of PD-related genes on gravity sensation, "arousal", central pattern generation of leg movements, or muscle. To address this problem, we have developed an assay for the fly proboscis extension response (PER). This is attractive because the PER has a simple, well-identified reflex neural circuit ... We conclude the Drosophila PER provides an excellent model of LRRK2 motor deficits showing bradykinesia, akinesia, hypokinesia, and increased tremor, with the possibility to localize changes in neural signaling."
Tuesday, November 21, 2017
Studies "launching from Drosophila models" provide insights into molecular mechanisms of ALS and FTD
Berson A, Sartoris A, Nativio R, Van Deerlin V, Toledo JB, Porta S, Liu S, Chung CY, Garcia BA, Lee VM, Trojanowski JQ, Johnson FB, Berger SL, Bonini NM. TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling. Curr Biol. 2017 Nov 9. pii: S0960-9822(17)31327-1. PMID: 29153328.
The abstract: "Regulation of chromatin structure is critical for brain development and function. However, the involvement of chromatin dynamics in neurodegeneration is less well understood. Here we find, launching from Drosophila models of amyotrophic lateral sclerosis and frontotemporal dementia, that TDP-43 impairs the induction of multiple key stress genes required to protect from disease by reducing the recruitment of the chromatin remodeler Chd1 to chromatin. Chd1 depletion robustly enhances TDP-43-mediated neurodegeneration and promotes the formation of stress granules. Conversely, upregulation of Chd1 restores nucleosomal dynamics, promotes normal induction of protective stress genes, and rescues stress sensitivity of TDP-43-expressing animals. TDP-43-mediated impairments are conserved in mammalian cells, and, importantly, the human ortholog CHD2 physically interacts with TDP-43 and is strikingly reduced in level in temporal cortex of human patient tissue. These findings indicate that TDP-43-mediated neurodegeneration causes impaired chromatin dynamics that prevents appropriate expression of protective genes through compromised function of the chromatin remodeler Chd1/CHD2. Enhancing chromatin dynamics may be a treatment approach to amyotrophic lateral scleorosis (ALS)/frontotemporal dementia (FTD)."
The abstract: "Regulation of chromatin structure is critical for brain development and function. However, the involvement of chromatin dynamics in neurodegeneration is less well understood. Here we find, launching from Drosophila models of amyotrophic lateral sclerosis and frontotemporal dementia, that TDP-43 impairs the induction of multiple key stress genes required to protect from disease by reducing the recruitment of the chromatin remodeler Chd1 to chromatin. Chd1 depletion robustly enhances TDP-43-mediated neurodegeneration and promotes the formation of stress granules. Conversely, upregulation of Chd1 restores nucleosomal dynamics, promotes normal induction of protective stress genes, and rescues stress sensitivity of TDP-43-expressing animals. TDP-43-mediated impairments are conserved in mammalian cells, and, importantly, the human ortholog CHD2 physically interacts with TDP-43 and is strikingly reduced in level in temporal cortex of human patient tissue. These findings indicate that TDP-43-mediated neurodegeneration causes impaired chromatin dynamics that prevents appropriate expression of protective genes through compromised function of the chromatin remodeler Chd1/CHD2. Enhancing chromatin dynamics may be a treatment approach to amyotrophic lateral scleorosis (ALS)/frontotemporal dementia (FTD)."
Monday, November 13, 2017
Review discusses use of Drosophila in studies of neurological diseases
Şentürk M, Bellen HJ. Genetic strategies to tackle neurological diseases in fruit flies. Curr Opin Neurobiol. 2017 Nov 8;50:24-32. PMID: 29128849.
The abstract: "Drosophila melanogaster is a genetic model organism that has contributed to the discovery of numerous genes whose human homologues are associated with diseases. The development of sophisticated genetic tools to manipulate its genome accelerates the discovery of the genetic basis of undiagnosed human diseases and the elucidation of molecular pathogenic events of known and novel diseases. Here, we discuss various approaches used in flies to assess the function of the fly homologues of disease-associated genes. We highlight how systematic and combinatorial approaches based on recently established methods provide us with integrated tool sets that can be applied to the study of neurodevelopmental and neurodegenerative disorders."
The abstract: "Drosophila melanogaster is a genetic model organism that has contributed to the discovery of numerous genes whose human homologues are associated with diseases. The development of sophisticated genetic tools to manipulate its genome accelerates the discovery of the genetic basis of undiagnosed human diseases and the elucidation of molecular pathogenic events of known and novel diseases. Here, we discuss various approaches used in flies to assess the function of the fly homologues of disease-associated genes. We highlight how systematic and combinatorial approaches based on recently established methods provide us with integrated tool sets that can be applied to the study of neurodevelopmental and neurodegenerative disorders."
Wednesday, November 8, 2017
Drosophila mode of Alzheimer's disease explores relevance of glial engulfment receptor Draper
Ray A, Speese SD, Logan MA. Glial Draper rescues Aβ toxicity in a Drosophila model of Alzheimer's Disease. J Neurosci. 2017 Nov 6. pii: 0862-17. PMID: 29109235.
From the abstract: "Pathological hallmarks of Alzheimer's disease (AD) include amyloid-beta (Aβ) plaques, neurofibrillary tangles, and reactive gliosis. Glial cells offer protection against AD by engulfing extracellular Aβ peptides, but the repertoire of molecules required for glial recognition and destruction of Aβ are still unclear. Here, we show that the highly conserved glial engulfment receptor Draper/MEGF10 provides neuroprotection in an AD model of Drosophila (both sexes). ... Here we show that the glial engulfment receptor Draper is protective in a Drosophila model of AD, reducing levels of amyloid beta (Aβ) peptides, reversing locomotor defects, and extending lifespan. We further show that protein degradation pathways are induced downstream of Draper in AD model flies, supporting a model in which glia engulf and destroy Aβ peptides to reduce amyloid-associated toxicity."
From the abstract: "Pathological hallmarks of Alzheimer's disease (AD) include amyloid-beta (Aβ) plaques, neurofibrillary tangles, and reactive gliosis. Glial cells offer protection against AD by engulfing extracellular Aβ peptides, but the repertoire of molecules required for glial recognition and destruction of Aβ are still unclear. Here, we show that the highly conserved glial engulfment receptor Draper/MEGF10 provides neuroprotection in an AD model of Drosophila (both sexes). ... Here we show that the glial engulfment receptor Draper is protective in a Drosophila model of AD, reducing levels of amyloid beta (Aβ) peptides, reversing locomotor defects, and extending lifespan. We further show that protein degradation pathways are induced downstream of Draper in AD model flies, supporting a model in which glia engulf and destroy Aβ peptides to reduce amyloid-associated toxicity."
Fly studies contribute to understanding of Brown-Vialetto-Van Laere syndrome with implications for a possible treatment strategy
Manole A, Jaunmuktane Z, Hargreaves I, Ludtmann MHR, Salpietro V, Bello OD, Pope S, Pandraud A, Horga A, Scalco RS, Li A, Ashokkumar B, Lourenço CM, Heales S, Horvath R, Chinnery PF, Toro C, Singleton AB, Jacques TS, Abramov AY, Muntoni F, Hanna MG, Reilly MM, Revesz T, Kullmann DM, Jepson JEC, Houlden H. Clinical, pathological and functional characterization of riboflavin-responsive neuropathy. Brain. 2017 Nov 1;140(11):2820-2837. PMID: 29053833.
From the abstract: "Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. ... By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome ... global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity ... Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology ... Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy."
From the abstract: "Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. ... By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome ... global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity ... Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology ... Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy."
Fly research helps inform understanding of signal pathway roles in Schimke immuno-osseous dysplasia
Morimoto M, Myung C, Beirnes K, Choi K, Asakura Y, Bokenkamp A, Bonneau D, Brugnara M, Charrow J, Colin E, Davis A, Deschenes G, Gentile M, Giordano M, Gormley AK, Govender R, Joseph M, Keller K, Lerut E, Levtchenko E, Massella L, Mayfield C, Najafian B, Parham D, Spranger J, Stenzel P, Yis U, Yu Z, Zonana J, Hendson G, Boerkoel CF. Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia? Orphanet J Rare Dis. 2016 Nov 5;11(1):149. PMID: 27816064; PMCID: PMC5097426.
From the abstract: "Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. ... we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila. ... We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients."
From the abstract: "Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. ... we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila. ... We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients."
Monday, November 6, 2017
Drosophila studies inform understanding of cellular mechanisms underlying Snyder-Robinson syndrome
Li C, Brazill JM, Liu S, Bello C, Zhu Y, Morimoto M, Cascio L, Pauly R, Diaz-Perez Z, Malicdan MCV, Wang H, Boccuto L, Schwartz CE, Gahl WA, Boerkoel CF, Zhai RG. Spermine synthase deficiency causes lysosomal dysfunction and oxidative stress in models of Snyder-Robinson syndrome. Nat Commun. 2017 Nov 2;8(1):1257. PMID: 29097652.
From the abstract: "... Loss-of-function mutations in spermine synthase (SMS), a polyamine biosynthesis enzyme, cause Snyder-Robinson syndrome (SRS), an X-linked intellectual disability syndrome ... Here we show that loss of dSms in Drosophila recapitulates the pathological polyamine imbalance of SRS and causes survival defects and synaptic degeneration. ... Our findings uncover some of the mechanisms underlying the pathological consequences of abnormal polyamine metabolism in the nervous system and may provide potential therapeutic targets for treating SRS and other polyamine-associated neurological disorders."
From the abstract: "... Loss-of-function mutations in spermine synthase (SMS), a polyamine biosynthesis enzyme, cause Snyder-Robinson syndrome (SRS), an X-linked intellectual disability syndrome ... Here we show that loss of dSms in Drosophila recapitulates the pathological polyamine imbalance of SRS and causes survival defects and synaptic degeneration. ... Our findings uncover some of the mechanisms underlying the pathological consequences of abnormal polyamine metabolism in the nervous system and may provide potential therapeutic targets for treating SRS and other polyamine-associated neurological disorders."
Tuesday, October 31, 2017
Studies in flies and mice implicate glycation in neurodegenerative disease-associated protein toxicity
Vicente Miranda H, Szego ÉM, Oliveira LMA, Breda C, Darendelioglu E, de Oliveira RM, Ferreira DG, Gomes MA, Rott R, Oliveira M, Munari F, Enguita FJ,Simões T, Rodrigues EF, Heinrich M, Martins IC, Zamolo I, Riess O, Cordeiro C, Ponces-Freire A, Lashuel HA, Santos NC, Lopes LV, Xiang W, Jovin TM, Penque D, Engelender S, Zweckstetter M, Klucken J, Giorgini F, Quintas A, Outeiro TF. Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies. Brain. 2017 May 1;140(5):1399-1419. PMID: 28398476.
From the abstract: "α-Synuclein misfolding and aggregation is a hallmark in Parkinson's disease and in several other neurodegenerative diseases known as synucleinopathies. ... Combining molecular genetics with target-based approaches, we established that glycation, an unavoidable age-associated post-translational modification, enhanced α-synuclein toxicity in vitro and in vivo, in Drosophila and in mice. ... Altogether, our study demonstrates glycation constitutes a novel drug target that can be explored in synucleinopathies as well as in other neurodegenerative conditions."
From the abstract: "α-Synuclein misfolding and aggregation is a hallmark in Parkinson's disease and in several other neurodegenerative diseases known as synucleinopathies. ... Combining molecular genetics with target-based approaches, we established that glycation, an unavoidable age-associated post-translational modification, enhanced α-synuclein toxicity in vitro and in vivo, in Drosophila and in mice. ... Altogether, our study demonstrates glycation constitutes a novel drug target that can be explored in synucleinopathies as well as in other neurodegenerative conditions."
Monday, October 16, 2017
Detailed molecular mechanistic study related to insulin resistance
Fischer Z, Das R, Shipman A, Fan JY, Pence L, Bouyain S, Dobens LL. A Drosophila model of insulin resistance associated with the human Trib3 Q/R polymorphism. Dis Model Mech. 2017 Oct 12. pii: dmm.030619. doi: 10.1242/dmm.030619. PMID: 29025897.
From the abstract: "Members of the Tribbles family of proteins are conserved pseudokinases with diverse roles in cell growth and proliferation. Both Drosophila Tribbles (Trbl) and vertebrate Trib3 proteins bind to Akt kinase to block its phosphorylation-activation and reduce downstream insulin-stimulated anabolism. A single nucleotide polymorphism (SNP) variant in human Trib3, which results in a glutamine (Q) to arginine (R) missense mutation in a conserved motif at position 84, confers stronger Akt binding resulting in reduced Akt phosphorylation and is associated with a predisposition to Type II diabetes, cardiovascular disease, diabetic nephropathy, chronic kidney disease and leukemogenesis. Here we used a Drosophila model to understand the importance of the conserved R residue in several Trbl functions. ..."
From the abstract: "Members of the Tribbles family of proteins are conserved pseudokinases with diverse roles in cell growth and proliferation. Both Drosophila Tribbles (Trbl) and vertebrate Trib3 proteins bind to Akt kinase to block its phosphorylation-activation and reduce downstream insulin-stimulated anabolism. A single nucleotide polymorphism (SNP) variant in human Trib3, which results in a glutamine (Q) to arginine (R) missense mutation in a conserved motif at position 84, confers stronger Akt binding resulting in reduced Akt phosphorylation and is associated with a predisposition to Type II diabetes, cardiovascular disease, diabetic nephropathy, chronic kidney disease and leukemogenesis. Here we used a Drosophila model to understand the importance of the conserved R residue in several Trbl functions. ..."
Drosophila research contributes to understanding of genetic factors relevant to chronic mountain sickness
Stobdan T, Akbari A, Azad P, Zhou D, Poulsen O, Appenzeller O, Gonzales GF, Telenti A, Wong EHM, Saini S, Kirkness EF, Venter JC, Bafna V, Haddad GG. New insights into the genetic basis of Monge's disease and adaptation to high-altitude. Mol Biol Evol. 2017 Sep 19. doi: 10.1093/molbev/msx239. PMID: 29029226.
From the abstract: "Human high-altitude (HA) adaptation or mal-adaptation is explored to understand the physiology, pathophysiology and molecular mechanisms that underlie long-term exposure to hypoxia. Here we report the results of an analysis of the largest whole-genome-sequencing of Chronic Mountain Sickness (CMS) [also known as Monge's disease] and non-CMS individuals, identified candidate genes and functionally validated these candidates in a genetic model system (Drosophila). ... examination of individual genes in these regions revealed the involvement of previously identified candidates (e.g., SENP1) and also unreported ones SGK3, COPS5, PRDM1 and IFT122 in CMS. Remarkably, in addition to genes like SENP1, SGK3 and COPS5 which are HIF-dependent, our study reveals for the first time HIF-independent gene PRDM1, indicating an involvement of wider, non-HIF pathways in HA adaptation. Finally, we observed that down-regulating orthologs of these genes in Drosophila significantly enhanced their hypoxia tolerance. ... Since the overwhelming majority of SNPs are in non-exonic (and possibly regulatory) regions, we speculate that adaptation to HA necessitates greater genetic flexibility allowing for transcript variability in response to graded levels of hypoxia."
From the abstract: "Human high-altitude (HA) adaptation or mal-adaptation is explored to understand the physiology, pathophysiology and molecular mechanisms that underlie long-term exposure to hypoxia. Here we report the results of an analysis of the largest whole-genome-sequencing of Chronic Mountain Sickness (CMS) [also known as Monge's disease] and non-CMS individuals, identified candidate genes and functionally validated these candidates in a genetic model system (Drosophila). ... examination of individual genes in these regions revealed the involvement of previously identified candidates (e.g., SENP1) and also unreported ones SGK3, COPS5, PRDM1 and IFT122 in CMS. Remarkably, in addition to genes like SENP1, SGK3 and COPS5 which are HIF-dependent, our study reveals for the first time HIF-independent gene PRDM1, indicating an involvement of wider, non-HIF pathways in HA adaptation. Finally, we observed that down-regulating orthologs of these genes in Drosophila significantly enhanced their hypoxia tolerance. ... Since the overwhelming majority of SNPs are in non-exonic (and possibly regulatory) regions, we speculate that adaptation to HA necessitates greater genetic flexibility allowing for transcript variability in response to graded levels of hypoxia."
Monday, October 9, 2017
Experiments in Drosophila contribute to study of rare brain malformation
Cavallin M, Rujano MA, Bednarek N, Medina-Cano D, Bernabe Gelot A, Drunat S, Maillard C, Garfa-Traore M, Bole C, Nitschké P, Beneteau C, Besnard T, Cogné B, Eveillard M, Kuster A, Poirier K, Verloes A, Martinovic J, Bidat L, Rio M, Lyonnet S, Reilly ML, Boddaert N, Jenneson-Liver M, Motte J, Doco-Fenzy M, Chelly J, Attie-Bitach T, Simons M, Cantagrel V, Passemard S, Baffet A, Thomas S, Bahi-Buisson N. WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells. Brain. 2017 Oct 1;140(10):2597-2609. doi: 10.1093/brain/awx218. PubMed PMID: 28969387.
From the abstract: "Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors ... [but] the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. ... we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans."
From the abstract: "Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors ... [but] the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. ... we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans."
Monday, October 2, 2017
Nobel Prize to Drosophila researchers
The Nobel Prize for physiology or medicine 2017 has been awarded to three Drosophila researchers, J.C. Hall, M. Rosbash, and M.W. Young, for their work uncovering molecular mechanisms of circadian rhythms. Read more at the the Nobel Prize website.
Wednesday, August 23, 2017
Drosophila as a model for understanding genetic links to our responses to environmental toxins
A Drosophila model for toxicogenomics: Genetic variation in susceptibility to heavy metal exposure.
Shanshan Zhou, Sarah E. Luoma, Genevieve E. St. Armour, Esha Thakkar, Trudy F. C. Mackay, Robert R. H. Anholt
In PLoS Genetics 2017
From the author summary: "Although physiological effects of environmental toxins are well documented, we know little about the genetic factors that determine individual variation in susceptibility to toxins. Such information is difficult to obtain in human populations due to heterogeneity in genetic background and environmental exposure, and the diversity of symptoms and time lag with which they appear after toxic exposure. Here, we show that the fruit fly, Drosophila, can serve as a powerful genetic model system to elucidate the genetic underpinnings that contribute to individual variation in resistance to toxicity, using lead and cadmium exposure as an experimental paradigm. ... Thus, we demonstrate that based on evolutionary conservation of fundamental biological processes, we can use Drosophila as a powerful translational model for toxicogenomics studies."
Shanshan Zhou, Sarah E. Luoma, Genevieve E. St. Armour, Esha Thakkar, Trudy F. C. Mackay, Robert R. H. Anholt
In PLoS Genetics 2017
From the author summary: "Although physiological effects of environmental toxins are well documented, we know little about the genetic factors that determine individual variation in susceptibility to toxins. Such information is difficult to obtain in human populations due to heterogeneity in genetic background and environmental exposure, and the diversity of symptoms and time lag with which they appear after toxic exposure. Here, we show that the fruit fly, Drosophila, can serve as a powerful genetic model system to elucidate the genetic underpinnings that contribute to individual variation in resistance to toxicity, using lead and cadmium exposure as an experimental paradigm. ... Thus, we demonstrate that based on evolutionary conservation of fundamental biological processes, we can use Drosophila as a powerful translational model for toxicogenomics studies."
Monday, August 14, 2017
Fly study of 14 candidate ADHD genes
Rohde PD, Madsen LS, Neumann Arvidson SM, Loeschcke V, Demontis D, Kristensen TN. Testing candidate genes for attention-deficit/hyperactivity disorder in fruit flies using a high throughput assay for complex behavior. Fly (Austin). 2016 Jan 2;10(1):25-34. PMID: 26954609; PMCID: PMC4934711.
From the abstract: "... Here we use a high-throughput locomotor activity assay to test the response on activity behavior of gene disruption in Drosophila melanogaster. The aim was to investigate the impact of disruption of 14 candidate genes for human attention-deficit/hyperactivity disorder (ADHD) on fly behavior. By obtaining a range of correlated measures describing the space of variables for behavioral activity we show, that some mutants display similar phenotypic responses, and furthermore, that the genes disrupted in those mutants had common molecular functions; namely processes related to cGMP activity, cation channels and serotonin receptors. ... Results provide additional support for the investigated genes being risk candidate genes for ADHD in humans."
From the abstract: "... Here we use a high-throughput locomotor activity assay to test the response on activity behavior of gene disruption in Drosophila melanogaster. The aim was to investigate the impact of disruption of 14 candidate genes for human attention-deficit/hyperactivity disorder (ADHD) on fly behavior. By obtaining a range of correlated measures describing the space of variables for behavioral activity we show, that some mutants display similar phenotypic responses, and furthermore, that the genes disrupted in those mutants had common molecular functions; namely processes related to cGMP activity, cation channels and serotonin receptors. ... Results provide additional support for the investigated genes being risk candidate genes for ADHD in humans."
Monday, July 17, 2017
Fly research and neurodegenerative diseases
Research articles related to ALS and Alzheimer's disease
Baldwin KR, Godena VK, Hewitt VL, Whitworth AJ. Axonal transport defects are a common phenotype in Drosophila models of ALS. Hum Mol Genet. 2016 Jun 15;25(12):2378-2392. Epub 2016 Apr 7. PMID: 27056981; PMCID: PMC5181624.
From the abstract: "Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of motor neurons resulting in a catastrophic loss of motor function. Current therapies are severely limited owing to a poor mechanistic understanding of the pathobiology. Mutations in a large number of genes have now been linked to ALS, including SOD1, TARDBP (TDP-43), FUS and C9orf72. Functional analyses of these genes and their pathogenic mutations have provided great insights into the underlying disease mechanisms. Defective axonal transport is hypothesized to be a key factor in the selective vulnerability of motor nerves ... Here, we assessed the axonal transport of different cargos in multiple Drosophila models of ALS. ... These results further support defects in axonal transport as a common factor in models of ALS that may contribute to the pathogenic process."
Bernstein AI, Lin Y, Street RC, Lin L, Dai Q, Yu L, Bao H, Gearing M, Lah JJ, Nelson PT, He C, Levey AI, Mullé JG, Duan R, Jin P. 5-Hydroxymethylation-associated epigenetic modifiers of Alzheimer's disease modulate Tau-induced neurotoxicity. Hum Mol Genet. 2016 Jun 15;25(12):2437-2450. PMID: 27060332; PMCID: PMC5181627.
From the abstract: "Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive deterioration of cognitive function. Pathogenesis of AD is incompletely understood; evidence suggests a role for epigenetic regulation, in particular the cytosine modifications 5-methylcytosine and 5-hydroxymethylcytosine (5hmC). 5hmC is enriched in the nervous system and displays neurodevelopment and age-related changes. To determine the role of 5hmC in AD, we performed genome-wide analyses of 5hmC in DNA from prefrontal cortex of post-mortem AD patients, and RNA-Seq to correlate changes in 5hmC with transcriptional changes. We identified 325 genes containing differentially hydroxymethylated loci (DhMLs) in both discovery and replication datasets. ... Finally, using an existing AD fly model, we showed some of these genes modulate AD-associated toxicity. ..."
And a review related to Parkinson's disease
Voigt A, Berlemann LA, Winklhofer KF. The mitochondrial kinase PINK1: functions beyond mitophagy. J Neurochem. 2016 Oct;139 Suppl 1:232-239. PMID: 27251035.
From the abstract: "Mutations in the genes encoding the mitochondrial kinase PINK1 and the E3 ubiquitin ligase Parkin cause autosomal recessive Parkinson's disease (PD). Pioneering work in Drosophila melanogaster revealed that the loss of PINK1 or Parkin function causes similar phenotypes including dysfunctional mitochondria. Further research showed that PINK1 can act upstream of Parkin in a mitochondrial quality control pathway to induce removal of damaged mitochondria in a process called mitophagy. ... In this review, we summarize and discuss the functional roles of PINK1 in maintaining mitochondrial integrity, eliminating damaged mitochondria, and promoting cell survival. This article is part of a special issue on Parkinson disease."
Baldwin KR, Godena VK, Hewitt VL, Whitworth AJ. Axonal transport defects are a common phenotype in Drosophila models of ALS. Hum Mol Genet. 2016 Jun 15;25(12):2378-2392. Epub 2016 Apr 7. PMID: 27056981; PMCID: PMC5181624.
From the abstract: "Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of motor neurons resulting in a catastrophic loss of motor function. Current therapies are severely limited owing to a poor mechanistic understanding of the pathobiology. Mutations in a large number of genes have now been linked to ALS, including SOD1, TARDBP (TDP-43), FUS and C9orf72. Functional analyses of these genes and their pathogenic mutations have provided great insights into the underlying disease mechanisms. Defective axonal transport is hypothesized to be a key factor in the selective vulnerability of motor nerves ... Here, we assessed the axonal transport of different cargos in multiple Drosophila models of ALS. ... These results further support defects in axonal transport as a common factor in models of ALS that may contribute to the pathogenic process."
Bernstein AI, Lin Y, Street RC, Lin L, Dai Q, Yu L, Bao H, Gearing M, Lah JJ, Nelson PT, He C, Levey AI, Mullé JG, Duan R, Jin P. 5-Hydroxymethylation-associated epigenetic modifiers of Alzheimer's disease modulate Tau-induced neurotoxicity. Hum Mol Genet. 2016 Jun 15;25(12):2437-2450. PMID: 27060332; PMCID: PMC5181627.
From the abstract: "Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive deterioration of cognitive function. Pathogenesis of AD is incompletely understood; evidence suggests a role for epigenetic regulation, in particular the cytosine modifications 5-methylcytosine and 5-hydroxymethylcytosine (5hmC). 5hmC is enriched in the nervous system and displays neurodevelopment and age-related changes. To determine the role of 5hmC in AD, we performed genome-wide analyses of 5hmC in DNA from prefrontal cortex of post-mortem AD patients, and RNA-Seq to correlate changes in 5hmC with transcriptional changes. We identified 325 genes containing differentially hydroxymethylated loci (DhMLs) in both discovery and replication datasets. ... Finally, using an existing AD fly model, we showed some of these genes modulate AD-associated toxicity. ..."
And a review related to Parkinson's disease
Voigt A, Berlemann LA, Winklhofer KF. The mitochondrial kinase PINK1: functions beyond mitophagy. J Neurochem. 2016 Oct;139 Suppl 1:232-239. PMID: 27251035.
From the abstract: "Mutations in the genes encoding the mitochondrial kinase PINK1 and the E3 ubiquitin ligase Parkin cause autosomal recessive Parkinson's disease (PD). Pioneering work in Drosophila melanogaster revealed that the loss of PINK1 or Parkin function causes similar phenotypes including dysfunctional mitochondria. Further research showed that PINK1 can act upstream of Parkin in a mitochondrial quality control pathway to induce removal of damaged mitochondria in a process called mitophagy. ... In this review, we summarize and discuss the functional roles of PINK1 in maintaining mitochondrial integrity, eliminating damaged mitochondria, and promoting cell survival. This article is part of a special issue on Parkinson disease."
Fly research & heart disease -- a review
Ma L. Can the Drosophila model help in paving the way for translational medicine in heart failure? Biochem Soc Trans. 2016 Oct 15;44(5):1549-1560. Review. PMID: 27911738.
Wednesday, July 12, 2017
No internal skeleton? No problem. The fly grainyhead gene informs our understanding of craniofacial defects
Carpinelli MR, de Vries ME, Jane SM, Dworkin S. Grainyhead-like Transcription Factors in Craniofacial Development. J Dent Res. 2017 Jul 1:22034517719264. PMID: 28697314.
The abstract: "Craniofacial development in vertebrates involves the coordinated growth, migration, and fusion of several facial prominences during embryogenesis, processes governed by strict genetic and molecular controls. A failure in any of the precise spatiotemporal sequences of events leading to prominence fusion often leads to anomalous facial, skull, and jaw formation-conditions termed craniofacial defects (CFDs). Affecting approximately 0.1% to 0.3% of live births, CFDs are a highly heterogeneous class of developmental anomalies, which are often underpinned by genetic mutations. Therefore, identifying novel disease-causing mutations in genes that regulate craniofacial development is a critical prerequisite to develop new preventive or therapeutic measures. The Grainyhead-like (GRHL) transcription factors are one such gene family, performing evolutionarily conserved roles in craniofacial patterning. The antecedent member of this family, Drosophila grainyhead (grh), is required for head skeleton development in fruit flies, loss or mutation of Grhl family members in mouse and zebrafish models leads to defects of both maxilla and mandible, and recently, mutations in human GRHL3 have been shown to cause or contribute to both syndromic (Van Der Woude syndrome) and nonsyndromic palatal clefts. In this review, we summarize the current knowledge regarding the craniofacial-specific function of the Grainyhead-like family in multiple model species, identify some of the major target genes regulated by the Grhl transcription factors in craniofacial patterning, and, by examining animal models, draw inferences as to how these data will inform the likely roles of GRHL factors in human CFDs comprising palatal clefting. By understanding the molecular networks regulated by Grhl2 and Grhl3 target genes in other systems, we can propose likely pathways that mediate the effects of these transcription factors in human palatogenesis."
The abstract: "Craniofacial development in vertebrates involves the coordinated growth, migration, and fusion of several facial prominences during embryogenesis, processes governed by strict genetic and molecular controls. A failure in any of the precise spatiotemporal sequences of events leading to prominence fusion often leads to anomalous facial, skull, and jaw formation-conditions termed craniofacial defects (CFDs). Affecting approximately 0.1% to 0.3% of live births, CFDs are a highly heterogeneous class of developmental anomalies, which are often underpinned by genetic mutations. Therefore, identifying novel disease-causing mutations in genes that regulate craniofacial development is a critical prerequisite to develop new preventive or therapeutic measures. The Grainyhead-like (GRHL) transcription factors are one such gene family, performing evolutionarily conserved roles in craniofacial patterning. The antecedent member of this family, Drosophila grainyhead (grh), is required for head skeleton development in fruit flies, loss or mutation of Grhl family members in mouse and zebrafish models leads to defects of both maxilla and mandible, and recently, mutations in human GRHL3 have been shown to cause or contribute to both syndromic (Van Der Woude syndrome) and nonsyndromic palatal clefts. In this review, we summarize the current knowledge regarding the craniofacial-specific function of the Grainyhead-like family in multiple model species, identify some of the major target genes regulated by the Grhl transcription factors in craniofacial patterning, and, by examining animal models, draw inferences as to how these data will inform the likely roles of GRHL factors in human CFDs comprising palatal clefting. By understanding the molecular networks regulated by Grhl2 and Grhl3 target genes in other systems, we can propose likely pathways that mediate the effects of these transcription factors in human palatogenesis."
Monday, July 10, 2017
Metal-related diseases studied using Drosophila
Calap-Quintana P, González-Fernández J, Sebastiá-Ortega N, Llorens JV, Moltó MD. Drosophila melanogaster Models of Metal-Related Human Diseases and Metal Toxicity. Int J Mol Sci. 2017 Jul 6;18(7). pii: E1456. PMID: 28684721.
From the abstract: "Iron, copper and zinc are transition metals essential for life ... Organisms have evolved to acquire metals from nutrition and to maintain adequate levels of each metal to avoid damaging effects associated with its deficiency, excess or misplacement. ... many orthologues of the human metal-related genes having been identified and characterized in Drosophila melanogaster. Drosophila has gained appreciation as a useful model for studying human diseases, including those caused by mutations in pathways controlling cellular metal homeostasis. ... This review recapitulates the metabolism of the principal transition metals, namely iron, zinc and copper, in Drosophila and the utility of this organism as an experimental model to explore the role of metal dyshomeostasis in different human diseases. Finally, a summary of the contribution of Drosophila as a model for testing metal toxicity is provided."
From the abstract: "Iron, copper and zinc are transition metals essential for life ... Organisms have evolved to acquire metals from nutrition and to maintain adequate levels of each metal to avoid damaging effects associated with its deficiency, excess or misplacement. ... many orthologues of the human metal-related genes having been identified and characterized in Drosophila melanogaster. Drosophila has gained appreciation as a useful model for studying human diseases, including those caused by mutations in pathways controlling cellular metal homeostasis. ... This review recapitulates the metabolism of the principal transition metals, namely iron, zinc and copper, in Drosophila and the utility of this organism as an experimental model to explore the role of metal dyshomeostasis in different human diseases. Finally, a summary of the contribution of Drosophila as a model for testing metal toxicity is provided."
Wednesday, June 7, 2017
Review highlights successful fly research collaborations with clinical impact
Chao HT, Liu L, Bellen HJ. Building dialogues between clinical and biomedical research through cross-species collaborations. Semin Cell Dev Biol. 2017 Jun 1. PMID: 28579453.
The abstract: "Today, biomedical science is equipped with an impressive array of technologies and genetic resources that bolster our basic understanding of fundamental biology and enhance the practice of modern medicine by providing clinicians with a diverse toolkit to diagnose, prognosticate, and treat a plethora of conditions. Many significant advances in our understanding of disease mechanisms and therapeutic interventions have arisen from fruitful dialogues between clinicians and biomedical research scientists. However, the increasingly specialized scientific and medical disciplines, globalization of science and technology, and complex datasets often hinder the development of effective interdisciplinary collaborations between clinical medicine and biomedical research. The goal of this review is to provide examples of diverse strategies to enhance communication and collaboration across diverse disciplines. First, we discuss examples of efforts to foster interdisciplinary collaborations at institutional and multi-institutional levels. Second, we explore resources and tools for clinicians and research scientists to facilitate effective bi-directional dialogues. Third, we use our experiences in neurobiology and human genetics to highlight how communication between clinical medicine and biomedical research lead to effective implementation of cross-species model organism approaches to uncover the biological underpinnings of health and disease."
The abstract: "Today, biomedical science is equipped with an impressive array of technologies and genetic resources that bolster our basic understanding of fundamental biology and enhance the practice of modern medicine by providing clinicians with a diverse toolkit to diagnose, prognosticate, and treat a plethora of conditions. Many significant advances in our understanding of disease mechanisms and therapeutic interventions have arisen from fruitful dialogues between clinicians and biomedical research scientists. However, the increasingly specialized scientific and medical disciplines, globalization of science and technology, and complex datasets often hinder the development of effective interdisciplinary collaborations between clinical medicine and biomedical research. The goal of this review is to provide examples of diverse strategies to enhance communication and collaboration across diverse disciplines. First, we discuss examples of efforts to foster interdisciplinary collaborations at institutional and multi-institutional levels. Second, we explore resources and tools for clinicians and research scientists to facilitate effective bi-directional dialogues. Third, we use our experiences in neurobiology and human genetics to highlight how communication between clinical medicine and biomedical research lead to effective implementation of cross-species model organism approaches to uncover the biological underpinnings of health and disease."
Friday, May 19, 2017
Flies used to test impact of retinal disease-relevant mutations on function of Crumbs family proteins
Pellikka M, Tepass U. Unique cell biological profiles of retinal disease-causing missense mutations in the polarity protein crumbs. J Cell Sci. 2017 May 17. pii: jcs.197178. PMID: 28515229.
From the abstract: "Mutations in human CRB1 are a major cause of retinal disease that lead to blindness. CRB1 is a transmembrane protein found in the inner segment of photoreceptor cells (PRCs) and the apical membrane of Müller glia. The function of the extracellular region of CRB1 is poorly understood although more than 80 disease-causing missense mutations have been mapped to it. We have recreated four mutations in Drosophila Crumbs (Crb) that affect different extracellular domains. ... The mutant Crb isoforms showed a remarkable diversity in protein abundance, subcellular distribution, and ability to rescue the lack of endogenous Crb, elicit a gain-of-function phenotype, or promote PRC degeneration. Interestingly, although expression of mutant isoforms rescued developmental defects of crb mutants substantially, they accelerated PRC degeneration compared to retinas that lack Crb ... Several Crb mutant proteins accumulated abnormally in the rhabdomere and affected rhodopsin trafficking, suggesting that abnormal rhodopsin physiology contributes to Crb/CRB1-dependent retinal degeneration."
From the abstract: "Mutations in human CRB1 are a major cause of retinal disease that lead to blindness. CRB1 is a transmembrane protein found in the inner segment of photoreceptor cells (PRCs) and the apical membrane of Müller glia. The function of the extracellular region of CRB1 is poorly understood although more than 80 disease-causing missense mutations have been mapped to it. We have recreated four mutations in Drosophila Crumbs (Crb) that affect different extracellular domains. ... The mutant Crb isoforms showed a remarkable diversity in protein abundance, subcellular distribution, and ability to rescue the lack of endogenous Crb, elicit a gain-of-function phenotype, or promote PRC degeneration. Interestingly, although expression of mutant isoforms rescued developmental defects of crb mutants substantially, they accelerated PRC degeneration compared to retinas that lack Crb ... Several Crb mutant proteins accumulated abnormally in the rhabdomere and affected rhodopsin trafficking, suggesting that abnormal rhodopsin physiology contributes to Crb/CRB1-dependent retinal degeneration."
Tuesday, May 16, 2017
Experiments in flies contribute to study of Renpenning syndrome
Zhang XY, Qi J, Shen YQ, Liu X, Liu A, Zhou Z, Han J, Zhang ZC. Mutations of PQBP1 in Renpenning syndrome promote ubiquitin-mediated degradation of FMRP and cause synaptic dysfunction. Hum Mol Genet. 2017 Mar 1;26(5):955-968. PMID: 28073926.
From the abstract: "Renpenning syndrome is a group of X-linked intellectual disability syndromes caused by mutations in human polyglutamine-binding protein 1 (PQBP1) gene. ... In this study, we examine the cellular and synaptic functions of the most common mutations found in the patients ... In Drosophila neuromuscular junction model, PQBP1 c.463_464dupAG transgenic flies showed remarkable defects of synaptic over-growth, which can be rescued by exogenously expressing dFMRP. Our data strongly support a gain-of-function pathogenic mechanism of PQBP1 c.459_462delAGAG and c.463_464dupAG mutations, and suggest that therapeutic strategies to restore FMRP function may be beneficial for those patients."
From the abstract: "Renpenning syndrome is a group of X-linked intellectual disability syndromes caused by mutations in human polyglutamine-binding protein 1 (PQBP1) gene. ... In this study, we examine the cellular and synaptic functions of the most common mutations found in the patients ... In Drosophila neuromuscular junction model, PQBP1 c.463_464dupAG transgenic flies showed remarkable defects of synaptic over-growth, which can be rescued by exogenously expressing dFMRP. Our data strongly support a gain-of-function pathogenic mechanism of PQBP1 c.459_462delAGAG and c.463_464dupAG mutations, and suggest that therapeutic strategies to restore FMRP function may be beneficial for those patients."
Crystal structure of fly protein reveals new functional information relevant to epilepsy and DOOR syndrome
Fischer B, Lüthy K, Paesmans J, De Koninck C, Maes I, Swerts J, Kuenen S, Uytterhoeven V, Verstreken P, Versées W. Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function. Nat Struct Mol Biol. 2016 Nov;23(11):965-973. PMID: 27669036.
From the abstract: "Mutations in TBC1D24 cause severe epilepsy and DOORS syndrome, but the molecular mechanisms underlying these pathologies are unresolved. We solved the crystal structure of the TBC domain of the Drosophila ortholog Skywalker, revealing an unanticipated cationic pocket conserved among TBC1D24 homologs. ... The most prevalent patient mutations affect the phosphoinositide-binding pocket and inhibit lipid binding. ... Hence, we discovered that a TBC domain affected by clinical mutations directly binds phosphoinositides through a cationic pocket and that phosphoinositide binding is critical for presynaptic function."
From the abstract: "Mutations in TBC1D24 cause severe epilepsy and DOORS syndrome, but the molecular mechanisms underlying these pathologies are unresolved. We solved the crystal structure of the TBC domain of the Drosophila ortholog Skywalker, revealing an unanticipated cationic pocket conserved among TBC1D24 homologs. ... The most prevalent patient mutations affect the phosphoinositide-binding pocket and inhibit lipid binding. ... Hence, we discovered that a TBC domain affected by clinical mutations directly binds phosphoinositides through a cationic pocket and that phosphoinositide binding is critical for presynaptic function."
Thursday, April 20, 2017
Review article: the fly as "powerful system for the study of human genetic disease"
Chow CY, Reiter LT. Etiology of Human Genetic Disease on the Fly. Trends Genet. 2017 Apr 15. pii: S0168-9525(17)30051-3. PMID: 28420493.
Abstract: "The model organism Drosophila melanogaster has been at the forefront of genetic studies since before the discovery of DNA. Although human disease modeling in flies may still be rather novel, recent advances in genetic tool design and genome sequencing now confer huge advantages in the fly system when modeling human disease. In this review, we focus on new genomic tools for human gene variant analysis; new uses for the Drosophila Genetic Reference Panel (DGRP) in detection of background alleles that influence a phenotype; and several examples of how multigenic conditions, both complex disorders and duplication and/or deletion syndromes, can be effectively studied in the fly model system. Fruit flies are a far cry from the quaint genetic model of the past, but rather, continue to evolve as a powerful system for the study of human genetic disease."
Abstract: "The model organism Drosophila melanogaster has been at the forefront of genetic studies since before the discovery of DNA. Although human disease modeling in flies may still be rather novel, recent advances in genetic tool design and genome sequencing now confer huge advantages in the fly system when modeling human disease. In this review, we focus on new genomic tools for human gene variant analysis; new uses for the Drosophila Genetic Reference Panel (DGRP) in detection of background alleles that influence a phenotype; and several examples of how multigenic conditions, both complex disorders and duplication and/or deletion syndromes, can be effectively studied in the fly model system. Fruit flies are a far cry from the quaint genetic model of the past, but rather, continue to evolve as a powerful system for the study of human genetic disease."
Monday, April 10, 2017
Drosophila genetic screen identifies new candidate Alzheimer's-related genes
Belfiori-Carrasco LF, Marcora MS, Bocai NI, Ceriani MF, Morelli L, Castaño EM. A Novel Genetic Screen Identifies Modifiers of Age-Dependent Amyloid β Toxicity in the Drosophila Brain. Front Aging Neurosci. 2017 Mar 14;9:61. PMID: 28352227; PMCID: PMC5349081.
From the abstract: "The accumulation of amyloid β peptide (Aβ) in the brain of Alzheimer's disease (AD) patients begins many years before clinical onset. Such process has been proposed to be pathogenic through the toxicity of Aβ soluble oligomers leading to synaptic dysfunction, phospho-tau aggregation and neuronal loss. Yet, a massive accumulation of Aβ can be found in approximately 30% of aged individuals with preserved cognitive function. Therefore, within the frame of the "amyloid hypothesis", compensatory mechanisms and/or additional neurotoxic or protective factors need to be considered and investigated. Here we describe a modifier genetic screen in Drosophila designed to identify genes that modulate toxicity of Aβ42 in the CNS. ... Our screen is the first to take into account all of the following features, relevant to sporadic AD: (1) pan-neuronal expression of wild-type Aβ42; (2) a quantifiable complex behavior; (3) Aβ neurotoxicity associated with progressive accumulation of the peptide; and (4) improvement or worsening of climbing ability only evident in aged animals. One hundred and ninety-nine deficiency (Df) lines accounting for ~6300 genes were analyzed. ... So far, we have validated CG11796 and identified CG17249 as a strong candidate (whose human orthologs are HPD and PRCC, respectively) by using RNAi or mutant hemizygous lines. ... These previously undetected modifiers of Aβ42 neurotoxicity in Drosophila warrant further study to validate their possible role and significance in the pathogenesis of sporadic AD."
From the abstract: "The accumulation of amyloid β peptide (Aβ) in the brain of Alzheimer's disease (AD) patients begins many years before clinical onset. Such process has been proposed to be pathogenic through the toxicity of Aβ soluble oligomers leading to synaptic dysfunction, phospho-tau aggregation and neuronal loss. Yet, a massive accumulation of Aβ can be found in approximately 30% of aged individuals with preserved cognitive function. Therefore, within the frame of the "amyloid hypothesis", compensatory mechanisms and/or additional neurotoxic or protective factors need to be considered and investigated. Here we describe a modifier genetic screen in Drosophila designed to identify genes that modulate toxicity of Aβ42 in the CNS. ... Our screen is the first to take into account all of the following features, relevant to sporadic AD: (1) pan-neuronal expression of wild-type Aβ42; (2) a quantifiable complex behavior; (3) Aβ neurotoxicity associated with progressive accumulation of the peptide; and (4) improvement or worsening of climbing ability only evident in aged animals. One hundred and ninety-nine deficiency (Df) lines accounting for ~6300 genes were analyzed. ... So far, we have validated CG11796 and identified CG17249 as a strong candidate (whose human orthologs are HPD and PRCC, respectively) by using RNAi or mutant hemizygous lines. ... These previously undetected modifiers of Aβ42 neurotoxicity in Drosophila warrant further study to validate their possible role and significance in the pathogenesis of sporadic AD."
Thursday, April 6, 2017
Parallel studies in human induced pluripotent stem cells and Drosophila identify a potential new target for development of possible therapies for Parkinson's Disease
Zanon A, Kalvakuri S, Rakovic A, Foco L, Guida M, Schwienbacher C, Serafin A, Rudolph F, Trilck M, Grünewald A, Stanslowsky N, Wegner F, Giorgio V, Lavdas AA, Bodmer R, Pramstaller PP, Klein C, Hicks AA, Pichler I, Seibler P. SLP-2 interacts with Parkin in mitochondria and prevents mitochondrial dysfunction in Parkin-deficient human iPSC-derived neurons and Drosophila. Hum Mol Genet. 2017 Apr 3. PMID: 28379402.
From the abstract: "Mutations in the Parkin gene (PARK2) have been linked to a recessive form of Parkinson's disease (PD) characterized by the loss of dopaminergic neurons in the substantia nigra. Deficiencies of mitochondrial respiratory chain complex I activity have been observed in the substantia nigra of PD patients, and loss of Parkin results in the reduction of complex I activity shown in various cell and animal models. Using co-immunoprecipitation and proximity ligation assays on endogenous proteins, we demonstrate that Parkin interacts with mitochondrial Stomatin-like protein 2 (SLP-2), which also binds the mitochondrial lipid cardiolipin and functions in the assembly of respiratory chain proteins. ... In-vivo Drosophila studies showed a genetic interaction of Parkin and SLP-2, and further, tissue-specific or global overexpression of SLP-2 transgenes rescued parkin mutant phenotypes ... The physical and genetic interaction between Parkin and SLP-2 and the compensatory potential of SLP-2 suggest a functional epistatic relationship to Parkin and a protective role of SLP-2 in neurons. This finding places further emphasis on the significance of Parkin for the maintenance of mitochondrial function in neurons and provides a novel target for therapeutic strategies."
From the abstract: "Mutations in the Parkin gene (PARK2) have been linked to a recessive form of Parkinson's disease (PD) characterized by the loss of dopaminergic neurons in the substantia nigra. Deficiencies of mitochondrial respiratory chain complex I activity have been observed in the substantia nigra of PD patients, and loss of Parkin results in the reduction of complex I activity shown in various cell and animal models. Using co-immunoprecipitation and proximity ligation assays on endogenous proteins, we demonstrate that Parkin interacts with mitochondrial Stomatin-like protein 2 (SLP-2), which also binds the mitochondrial lipid cardiolipin and functions in the assembly of respiratory chain proteins. ... In-vivo Drosophila studies showed a genetic interaction of Parkin and SLP-2, and further, tissue-specific or global overexpression of SLP-2 transgenes rescued parkin mutant phenotypes ... The physical and genetic interaction between Parkin and SLP-2 and the compensatory potential of SLP-2 suggest a functional epistatic relationship to Parkin and a protective role of SLP-2 in neurons. This finding places further emphasis on the significance of Parkin for the maintenance of mitochondrial function in neurons and provides a novel target for therapeutic strategies."
Friday, March 24, 2017
Aggression among flies as a model behavior for studies related to human neurological disorders
Zwarts L, Vulsteke V, Buhl E, Hodge JJ, Callaerts P. SlgA, the homologue of the human schizophrenia associated PRODH gene, acts in clock neurons to regulate Drosophila aggression. Dis Model Mech. 2017 Mar 22. pii: dmm.027151. PMID: 28331058.
From the abstract: "Mutations in proline dehydrogenase (PRODH) are linked to behavioral alterations in schizophrenia ... We here establish a Drosophila model to study the role of PRODH in behavioral disorders. We ... show that knock-down and overexpression of human PRODH and slgA in the lateral neurons ventral (LNv) lead to altered aggressive behavior. SlgA acts in an isoform-specific manner and is regulated by casein kinase II (CkII). Our data suggest that these effects are, at least partially, due to effects on mitochondrial function. We thus show that precise regulation of proline metabolism is essential to drive normal behavior and we identify Drosophila aggression as a model behavior relevant for the study of mechanisms impaired in neuropsychiatric disorders."
From the abstract: "Mutations in proline dehydrogenase (PRODH) are linked to behavioral alterations in schizophrenia ... We here establish a Drosophila model to study the role of PRODH in behavioral disorders. We ... show that knock-down and overexpression of human PRODH and slgA in the lateral neurons ventral (LNv) lead to altered aggressive behavior. SlgA acts in an isoform-specific manner and is regulated by casein kinase II (CkII). Our data suggest that these effects are, at least partially, due to effects on mitochondrial function. We thus show that precise regulation of proline metabolism is essential to drive normal behavior and we identify Drosophila aggression as a model behavior relevant for the study of mechanisms impaired in neuropsychiatric disorders."
Thursday, March 23, 2017
Study of Ets96B/ETV5 connects obesity and bipolar disorder at a molecular level
Williams MJ, Klockars A, Eriksson A, Voisin S, Dnyansagar R, Wiemerslage L, Kasagiannis A, Akram M, Kheder S, Ambrosi V, Hallqvist E, Fredriksson R, Schiöth HB. The Drosophila ETV5 Homologue Ets96B: Molecular Link between Obesity and Bipolar Disorder. PLoS Genet. 2016 Jun 9;12(6):e1006104. PubMed PMID: 27280443; PubMed Central PMCID: PMC4900636.
From the abstract: "Several reports suggest obesity and bipolar disorder (BD) share some physiological and behavioural similarities. ... Here we demonstrate, using whole transcriptome analysis, that Drosophila Ets96B, homologue of obesity-linked gene ETV5, regulates cellular systems associated with obesity and BD. Consistent with a role in obesity and BD, loss of nervous system Ets96B during development increases triacylglyceride concentration, while inducing a heightened startle-response, as well as increasing hyperactivity and reducing sleep. Of notable interest, mouse Etv5 and Drosophila Ets96B are expressed in dopaminergic-rich regions, and loss of Ets96B specifically in dopaminergic neurons recapitulates the metabolic and behavioural phenotypes. Moreover, our data indicate Ets96B inhibits dopaminergic-specific neuroprotective systems. Additionally, we reveal that multiple SNPs in human ETV5 link to body mass index (BMI) and BD, providing further evidence for ETV5 as an important and novel molecular intermediate between obesity and BD. ... a connection between the obesity-linked gene ETV5 and bipolar disorder emphasizes a functional relationship between obesity and BD at the molecular level."
From the abstract: "Several reports suggest obesity and bipolar disorder (BD) share some physiological and behavioural similarities. ... Here we demonstrate, using whole transcriptome analysis, that Drosophila Ets96B, homologue of obesity-linked gene ETV5, regulates cellular systems associated with obesity and BD. Consistent with a role in obesity and BD, loss of nervous system Ets96B during development increases triacylglyceride concentration, while inducing a heightened startle-response, as well as increasing hyperactivity and reducing sleep. Of notable interest, mouse Etv5 and Drosophila Ets96B are expressed in dopaminergic-rich regions, and loss of Ets96B specifically in dopaminergic neurons recapitulates the metabolic and behavioural phenotypes. Moreover, our data indicate Ets96B inhibits dopaminergic-specific neuroprotective systems. Additionally, we reveal that multiple SNPs in human ETV5 link to body mass index (BMI) and BD, providing further evidence for ETV5 as an important and novel molecular intermediate between obesity and BD. ... a connection between the obesity-linked gene ETV5 and bipolar disorder emphasizes a functional relationship between obesity and BD at the molecular level."
Review article addresses the question, Can flies help us find plant-based medicines?
Panchal K, Tiwari AK. Drosophila melanogaster "a potential model organism" for identification of pharmacological properties of plants/plant-derived components. Biomed Pharmacother. 2017 Mar 18;89:1331-1345. PubMed PMID: 28320100.
From the abstract: "Plants/plant-derived components have been used from ancient times to treat/cure several human diseases. ... long time consumption cause serious health concerns such as hyperallergic reactions, liver damage, etc. ... The current review focuses on the potential of Drosophila melanogaster for the identification of medicinal/pharmacological properties associated with plants/plant-derived components."
From the abstract: "Plants/plant-derived components have been used from ancient times to treat/cure several human diseases. ... long time consumption cause serious health concerns such as hyperallergic reactions, liver damage, etc. ... The current review focuses on the potential of Drosophila melanogaster for the identification of medicinal/pharmacological properties associated with plants/plant-derived components."
Tuesday, January 24, 2017
Results of a study in Drosophila suggest the possible relevance of neuronal aneuploidy to Tau-associated neurodegeneration
Malmanche N, Dourlen P, Gistelinck M, Demiautte F, Link N, Dupont C, Vanden Broeck L, Werkmeister E, Amouyel P, Bongiovanni A, Bauderlique H, Moechars D, Royou A, Bellen HJ, Lafont F, Callaerts P, Lambert JC, Dermaut B. Developmental Expression of 4-Repeat-Tau Induces Neuronal Aneuploidy in Drosophila Tauopathy Models. Sci Rep. 2017 Jan 23;7:40764. PMID: 28112163.
From the abstract: "Tau-mediated neurodegeneration in Alzheimer's disease and tauopathies is generally assumed to start in a normally developed brain. However, several lines of evidence suggest that impaired Tau isoform expression during development could affect mitosis and ploidy in post-mitotic differentiated tissue. ... Here, we used genetic and cellular tools to study the link between 3R and 4R-Tau isoform expression, mitotic progression in neuronal progenitors and post-mitotic neuronal survival. Our results illustrated that the severity of Tau-induced adult phenotypes depends on 4R-Tau isoform expression during development. ... we found a high level of aneuploidy in post-mitotic differentiated tissue. ... our results suggested that neurodegeneration could be in part linked to neuronal aneuploidy caused by 4R-Tau expression during brain development."
From the abstract: "Tau-mediated neurodegeneration in Alzheimer's disease and tauopathies is generally assumed to start in a normally developed brain. However, several lines of evidence suggest that impaired Tau isoform expression during development could affect mitosis and ploidy in post-mitotic differentiated tissue. ... Here, we used genetic and cellular tools to study the link between 3R and 4R-Tau isoform expression, mitotic progression in neuronal progenitors and post-mitotic neuronal survival. Our results illustrated that the severity of Tau-induced adult phenotypes depends on 4R-Tau isoform expression during development. ... we found a high level of aneuploidy in post-mitotic differentiated tissue. ... our results suggested that neurodegeneration could be in part linked to neuronal aneuploidy caused by 4R-Tau expression during brain development."
Monday, January 23, 2017
Using flies to functionally validate candidate heart disease-related genes
Zhu JY, Fu Y, Nettleton M, Richman A, Han Z. High throughput in vivo functional validation of candidate congenital heart disease genes in Drosophila. Elife. 2017 Jan 13;6. pii: e22617. PMID: 28084990.
From the abstract: "... We developed a Drosophila-based functional system to screen candidate disease genes identified from Congenital Heart Disease (CHD) patients. 134 genes were tested in the Drosophila heart using RNAi-based gene silencing. Quantitative analyses of multiple cardiac phenotypes demonstrated essential structural, functional, and developmental roles for more than 70 genes ... We also demonstrated the use of Drosophila to evaluate cardiac phenotypes resulting from specific, patient-derived alleles of candidate disease genes. ... This approach has the potential to facilitate development of precision medicine approaches for CHD and other diseases associated with genetic factors."
From the abstract: "... We developed a Drosophila-based functional system to screen candidate disease genes identified from Congenital Heart Disease (CHD) patients. 134 genes were tested in the Drosophila heart using RNAi-based gene silencing. Quantitative analyses of multiple cardiac phenotypes demonstrated essential structural, functional, and developmental roles for more than 70 genes ... We also demonstrated the use of Drosophila to evaluate cardiac phenotypes resulting from specific, patient-derived alleles of candidate disease genes. ... This approach has the potential to facilitate development of precision medicine approaches for CHD and other diseases associated with genetic factors."
Review of drug discovery using model organisms including Drosophila
Strange K. Drug Discovery in Fish, Flies, and Worms. ILAR J. 2016 Dec;57(2):133-143. PMID: 28053067.
From the abstract: "Nonmammalian model organisms ... provide numerous experimental advantages for drug discovery including genetic and molecular tractability, amenability to high-throughput screening methods and reduced experimental costs and increased experimental throughput compared to traditional mammalian models. ... This review will provide an overview of C. elegans, Drosophila, and zebrafish biology and husbandry and will discuss how these models are being used for phenotype-based drug screening and for identification of drug targets and mechanisms of action. ..."
From the abstract: "Nonmammalian model organisms ... provide numerous experimental advantages for drug discovery including genetic and molecular tractability, amenability to high-throughput screening methods and reduced experimental costs and increased experimental throughput compared to traditional mammalian models. ... This review will provide an overview of C. elegans, Drosophila, and zebrafish biology and husbandry and will discuss how these models are being used for phenotype-based drug screening and for identification of drug targets and mechanisms of action. ..."
Wednesday, January 11, 2017
Modified fly cultured cells as a biotherapeutic? Study suggests this could one day be an effective approach
Roy DG, Power AT, Bourgeois-Daigneault MC, Falls T, Ferreira L, Stern A, Tanese de Souza C, McCart JA, Stojdl DF, Lichty BD, Atkins H, Auer RC, Bell JC, Le Boeuf F. Programmable insect cell carriers for systemic delivery of integrated cancer biotherapy. J Control Release. 2015 Dec 28;220(Pt A):210-21. PMID: 26482080.
From the abstract: "Due to cancer's genetic complexity, significant advances in the treatment of metastatic disease will require sophisticated, multi-pronged therapeutic approaches. Here we demonstrate the utility of a Drosophila melanogaster cell platform for the production and in vivo delivery of multi-gene biotherapeutic systems. We show that cultured Drosophila S2 cell carriers can stably propagate oncolytic viral therapeutics that are highly cytotoxic for mammalian cancer cells without adverse effects on insect cell viability or gene expression. Drosophila cell carriers administered systemically to immunocompetent animals trafficked to tumors to deliver multiple biotherapeutics with little apparent off-target tissue homing or toxicity, resulting in a therapeutic effect. ..."
From the abstract: "Due to cancer's genetic complexity, significant advances in the treatment of metastatic disease will require sophisticated, multi-pronged therapeutic approaches. Here we demonstrate the utility of a Drosophila melanogaster cell platform for the production and in vivo delivery of multi-gene biotherapeutic systems. We show that cultured Drosophila S2 cell carriers can stably propagate oncolytic viral therapeutics that are highly cytotoxic for mammalian cancer cells without adverse effects on insect cell viability or gene expression. Drosophila cell carriers administered systemically to immunocompetent animals trafficked to tumors to deliver multiple biotherapeutics with little apparent off-target tissue homing or toxicity, resulting in a therapeutic effect. ..."
Monday, January 9, 2017
Journal issue focuses on fly models of disease
A special issue of Current Topics in Developmental Biology (vol. 121, January 2017) focuses on fly models of human diseases. Check out the journal issue titles to see what specific diseases and disorders are discussed in these expert-level review articles.
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