Guida MC, Birse RT, Dall'Agnese A, Toto PC, Diop SB, Mai A, Adams PD, Puri PL, Bodmer R. Intergenerational inheritance of high fat diet-induced cardiac lipotoxicity in Drosophila. Nat Commun. 2019 Jan 14;10(1):193. PMID: 30643137; PMCID: PMC6331650.
From the abstract: "Obesity is strongly correlated with lipotoxic cardiomyopathy, heart failure and thus mortality. ... and increasing evidence suggests that the parents' nutritional status may predispose their offspring to lipotoxic cardiomyopathy. ... Here we report that cardiac dysfunction induced by high-fat-diet (HFD) persists for two subsequent generations in Drosophila and is associated with reduced expression of two key metabolic regulators, adipose triglyceride lipase (ATGL/bmm) and transcriptional cofactor PGC-1. We provide evidence that targeted expression of ATGL/bmm in the offspring of HFD-fed parents protects them, and the subsequent generation, from cardio-lipotoxicity. Furthermore, we find that intergenerational inheritance of lipotoxic cardiomyopathy correlates with elevated systemic H3K27 trimethylation. Lowering H3K27 trimethylation genetically or pharmacologically in the offspring of HFD-fed parents prevents cardiac pathology. This suggests that metabolic homeostasis is epigenetically regulated across generations."
Justice AE, Karaderi T, Highland HM, et al. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nat Genet. 2019 Feb 18. PMID: 30778226.
Abstract: "Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants."
Thursday, February 21, 2019
Tuesday, February 19, 2019
Preprint: New fly model of SeSAME syndrome
Posted December 2018 on the preprint server:
Ravi K Nadella, Anirudh Chellappa, Anand G Subramaniam, View ORCID ProfileAman Aggarwal, Ravi Prabhakar More, Mahalakshmi Dhana sekar, Srividya Shetty, Suriya Prakash, Nikhil Ratna, Vandana VP, Meera Purushotham, Jitender Saini, Biju Viswanath, Bindu PS, Madhu Nagappa, Bhupesh Mehta, Sanjeev Jain, View ORCID ProfileRamakrishnan Kannan
Novel KCNJ10 mutation identified in a SeSAME family compromise channel function and impairs Drosophila locomotor behavior
https://www.biorxiv.org/content/10.1101/506949v1
From the preprint abstract: "Deficits in the inwardly rectifying K channel, Kir4.1, cause SeSAME syndrome, autism spectrum disorders with seizures, multiple sclerosis, Huntington disease and Rett syndrome. ... We used whole exome sequencing (WES), channel physiology in patient-specific lymphoblastoid cells (LCLs) and established a Drosophila model to examine the functional effects of a KCNJ10 variant identified in SeSAME like family. ... Drosophila irk2 mutant, a human homolog of Kir4.1, exhibited impairment locomotion, shortened life span and age dependent degeneration of dopaminergic neurons in the adult brain. ... neural specific expression of either Kir4.1 or Irk2 alleviate irk2 mutant phenotypes, while the Kir4.1(T290A) and Irk2(T290A) mutant proteins failed to do so. These results imply the functional conservation of Kir4.1 across species thereby elevate the potential of using Drosophila model to improve our understanding of the SeSAME syndrome. ..."
Ravi K Nadella, Anirudh Chellappa, Anand G Subramaniam, View ORCID ProfileAman Aggarwal, Ravi Prabhakar More, Mahalakshmi Dhana sekar, Srividya Shetty, Suriya Prakash, Nikhil Ratna, Vandana VP, Meera Purushotham, Jitender Saini, Biju Viswanath, Bindu PS, Madhu Nagappa, Bhupesh Mehta, Sanjeev Jain, View ORCID ProfileRamakrishnan Kannan
Novel KCNJ10 mutation identified in a SeSAME family compromise channel function and impairs Drosophila locomotor behavior
https://www.biorxiv.org/content/10.1101/506949v1
From the preprint abstract: "Deficits in the inwardly rectifying K channel, Kir4.1, cause SeSAME syndrome, autism spectrum disorders with seizures, multiple sclerosis, Huntington disease and Rett syndrome. ... We used whole exome sequencing (WES), channel physiology in patient-specific lymphoblastoid cells (LCLs) and established a Drosophila model to examine the functional effects of a KCNJ10 variant identified in SeSAME like family. ... Drosophila irk2 mutant, a human homolog of Kir4.1, exhibited impairment locomotion, shortened life span and age dependent degeneration of dopaminergic neurons in the adult brain. ... neural specific expression of either Kir4.1 or Irk2 alleviate irk2 mutant phenotypes, while the Kir4.1(T290A) and Irk2(T290A) mutant proteins failed to do so. These results imply the functional conservation of Kir4.1 across species thereby elevate the potential of using Drosophila model to improve our understanding of the SeSAME syndrome. ..."
Preprint: Researchers compare among 14 fly models of Spinal Muscular Atrophy (SMA)
Posted November 2018 on the BioRxiv preprint server:
Ashlyn M. Spring, Amanda C. Raimer, Christine D. Hamilton, Michela J. Schillinger, A. Gregory Matera
Comprehensive modeling of Spinal Muscular Atrophy in Drosophila melanogaster
https://www.biorxiv.org/content/10.1101/394908v3
From the preprint abstract: "Spinal muscular atrophy (SMA) is a neurodegenerative disorder that affects motor neurons, primarily in young children. ... A systematic analysis of SMA-related phenotypes in the context of moderate alleles that more closely mimic the genetics of SMA has not been performed in the fly, leading to debate over the validity and translational value of this model. We therefore examined fourteen Drosophila lines expressing SMA patient-derived missense mutations in Smn ... on the basis of organismal viability and longevity, locomotor function, neuromuscular junction structure, and muscle health. In all cases, we observed phenotypes similar to those of SMA patients, including progressive loss of adult motor function. The severity of these defects is variable, and forms a broad spectrum across the fourteen lines examined, recapitulating the full range of phenotypic severity observed in human SMA. ... The results provide direct evidence that SMA-related locomotor decline can be reproduced in the fly and support the use of patient-derived SMN missense mutations as a comprehensive system for modeling SMA."
Ashlyn M. Spring, Amanda C. Raimer, Christine D. Hamilton, Michela J. Schillinger, A. Gregory Matera
Comprehensive modeling of Spinal Muscular Atrophy in Drosophila melanogaster
https://www.biorxiv.org/content/10.1101/394908v3
From the preprint abstract: "Spinal muscular atrophy (SMA) is a neurodegenerative disorder that affects motor neurons, primarily in young children. ... A systematic analysis of SMA-related phenotypes in the context of moderate alleles that more closely mimic the genetics of SMA has not been performed in the fly, leading to debate over the validity and translational value of this model. We therefore examined fourteen Drosophila lines expressing SMA patient-derived missense mutations in Smn ... on the basis of organismal viability and longevity, locomotor function, neuromuscular junction structure, and muscle health. In all cases, we observed phenotypes similar to those of SMA patients, including progressive loss of adult motor function. The severity of these defects is variable, and forms a broad spectrum across the fourteen lines examined, recapitulating the full range of phenotypic severity observed in human SMA. ... The results provide direct evidence that SMA-related locomotor decline can be reproduced in the fly and support the use of patient-derived SMN missense mutations as a comprehensive system for modeling SMA."
New fly model of motile cilia-related diseases
Zur Lage P, Newton FG, Jarman AP. Survey of the Ciliary Motility Machinery of Drosophila Sperm and Ciliated Mechanosensory Neurons Reveals Unexpected Cell-Type Specific Variations: A Model for Motile Ciliopathies. Front Genet. 2019 Feb 1;10:24. PMID: 30774648; PMCID: PMC6367277.
From the abstract: "... The molecular machinery of ciliary motility comprises a variety of cilium-specific dynein motor complexes along with other complexes that regulate their activity. Assembling the motors requires the function of dedicated "assembly factors" and transport processes. In humans, mutation of any one of at least 40 different genes encoding components of the motility apparatus causes Primary Ciliary Dyskinesia (PCD), a disease of defective ciliary motility. Recently, Drosophila has emerged as a model for motile cilia biology and motile ciliopathies. This is somewhat surprising as most Drosophila cells lack cilia, and motile cilia are confined to just two specialized cell types ... we survey the Drosophila genome for ciliary motility gene homologs, and ... find that the molecules of cilium motility are well conserved in Drosophila. ... Our work lays the foundation for the increasing use of Drosophila as an excellent model for new motile ciliary gene discovery and validation, for understanding motile cilium function and assembly, as well as understanding the nature of genetic defects underlying human motile ciliopathies."
From the abstract: "... The molecular machinery of ciliary motility comprises a variety of cilium-specific dynein motor complexes along with other complexes that regulate their activity. Assembling the motors requires the function of dedicated "assembly factors" and transport processes. In humans, mutation of any one of at least 40 different genes encoding components of the motility apparatus causes Primary Ciliary Dyskinesia (PCD), a disease of defective ciliary motility. Recently, Drosophila has emerged as a model for motile cilia biology and motile ciliopathies. This is somewhat surprising as most Drosophila cells lack cilia, and motile cilia are confined to just two specialized cell types ... we survey the Drosophila genome for ciliary motility gene homologs, and ... find that the molecules of cilium motility are well conserved in Drosophila. ... Our work lays the foundation for the increasing use of Drosophila as an excellent model for new motile ciliary gene discovery and validation, for understanding motile cilium function and assembly, as well as understanding the nature of genetic defects underlying human motile ciliopathies."
Friday, February 15, 2019
Results from Fly model of Alzheimer's disease suggests protective role for neuronal cell death
Coelho DS, Schwartz S, Merino MM, Hauert B, Topfel B, Tieche C, Rhiner C, Moreno E. Culling Less Fit Neurons Protects against Amyloid-β-Induced Brain Damage and Cognitive and Motor Decline. Cell Rep. 2018 Dec 26;25(13):3661-3673.e3. PMID: 30590040; PMCID: PMC6315112.
Abstract: "Alzheimer's disease (AD) is the most common form of dementia, impairing cognitive and motor functions. One of the pathological hallmarks of AD is neuronal loss, which is not reflected in mouse models of AD. Therefore, the role of neuronal death is still uncertain. Here, we used a Drosophila AD model expressing a secreted form of human amyloid-β42 peptide and showed that it recapitulates key aspects of AD pathology, including neuronal death and impaired long-term memory. We found that neuronal apoptosis is mediated by cell fitness-driven neuronal culling, which selectively eliminates impaired neurons from brain circuits. We demonstrated that removal of less fit neurons delays β-amyloid-induced brain damage and protects against cognitive and motor decline, suggesting that contrary to common knowledge, neuronal death may have a beneficial effect in AD."
Abstract: "Alzheimer's disease (AD) is the most common form of dementia, impairing cognitive and motor functions. One of the pathological hallmarks of AD is neuronal loss, which is not reflected in mouse models of AD. Therefore, the role of neuronal death is still uncertain. Here, we used a Drosophila AD model expressing a secreted form of human amyloid-β42 peptide and showed that it recapitulates key aspects of AD pathology, including neuronal death and impaired long-term memory. We found that neuronal apoptosis is mediated by cell fitness-driven neuronal culling, which selectively eliminates impaired neurons from brain circuits. We demonstrated that removal of less fit neurons delays β-amyloid-induced brain damage and protects against cognitive and motor decline, suggesting that contrary to common knowledge, neuronal death may have a beneficial effect in AD."
Wednesday, February 6, 2019
Review of fly models of Parkinson's disease (now at PubMed Central)
Nagoshi E. Drosophila Models of Sporadic Parkinson's Disease. Int J Mol Sci. 2018 Oct 26;19(11). pii: E3343. doi: 10.3390/ijms19113343. PMID: 30373150; PMCID: PMC6275057.
From the abstract: "Parkinson's disease (PD) is the most common cause of movement disorders ... It is increasingly recognized as a complex group of disorders ... With the exception of the rare monogenic forms, the majority of PD cases result from an interaction between multiple genetic and environmental risk factors. The search for these risk factors and the development of preclinical animal models are in progress ... This review summarizes the studies that capitalize on modeling sporadic (i.e., nonfamilial) PD using Drosophila melanogaster and discusses their methodologies, new findings, and future perspectives."
From the abstract: "Parkinson's disease (PD) is the most common cause of movement disorders ... It is increasingly recognized as a complex group of disorders ... With the exception of the rare monogenic forms, the majority of PD cases result from an interaction between multiple genetic and environmental risk factors. The search for these risk factors and the development of preclinical animal models are in progress ... This review summarizes the studies that capitalize on modeling sporadic (i.e., nonfamilial) PD using Drosophila melanogaster and discusses their methodologies, new findings, and future perspectives."
Tuesday, February 5, 2019
New fly model of mitochondrial disease
Lovero D, Giordano L, Marsano RM, Sanchez-Martinez A, Boukhatmi H, Drechsler M, Oliva M, Whitworth AJ, Porcelli D, Caggese C. Characterization of Drosophila ATPsynC mutants as a new model of mitochondrial ATP synthase disorders. PLoS One. 2018 Aug 10;13(8):e0201811. doi: 10.1371/journal.pone.0201811. eCollection 2018. PMID: 30096161; PMCID: PMC6086398.
From the abstract: "Mitochondrial disorders associated with genetic defects of the ATP synthase are among the most deleterious diseases of the neuromuscular system that primarily manifest in newborns. Nevertheless, the number of established animal models ... is limited. In this paper, we target the Drosophila melanogaster gene encoding for the ATP synthase subunit c, ATPsynC ... we isolated a set of mutations showing a wide range of effects, from larval lethality to complex pleiotropic phenotypes ... ATPsynC mutations impair ATP synthesis and mitochondrial morphology, and represent a powerful toolkit for the screening of genetic modifiers that can lead to potential therapeutic solutions. Furthermore, the molecular characterization of ATPsynC mutations allowed us ... to define three broad pathological consequences of mutations affecting the mitochondrial ATP synthase functionality in Drosophila: i) pre-adult lethality; ii) multi-trait pathology accompanied by early adult lethality; iii) multi-trait adult pathology. We finally predict plausible parallelisms with genetic defects of mitochondrial ATP synthase in humans."
From the abstract: "Mitochondrial disorders associated with genetic defects of the ATP synthase are among the most deleterious diseases of the neuromuscular system that primarily manifest in newborns. Nevertheless, the number of established animal models ... is limited. In this paper, we target the Drosophila melanogaster gene encoding for the ATP synthase subunit c, ATPsynC ... we isolated a set of mutations showing a wide range of effects, from larval lethality to complex pleiotropic phenotypes ... ATPsynC mutations impair ATP synthesis and mitochondrial morphology, and represent a powerful toolkit for the screening of genetic modifiers that can lead to potential therapeutic solutions. Furthermore, the molecular characterization of ATPsynC mutations allowed us ... to define three broad pathological consequences of mutations affecting the mitochondrial ATP synthase functionality in Drosophila: i) pre-adult lethality; ii) multi-trait pathology accompanied by early adult lethality; iii) multi-trait adult pathology. We finally predict plausible parallelisms with genetic defects of mitochondrial ATP synthase in humans."
Fly study explores autophagy and Zika virus infection
Liu Y, Gordesky-Gold B, Leney-Greene M, Weinbren NL, Tudor M, Cherry S. Inflammation-Induced, STING-Dependent Autophagy Restricts Zika Virus Infection in the Drosophila Brain. Cell Host Microbe. 2018 Jul 11;24(1):57-68.e3. PMID: 29934091
Abstract: "The emerging arthropod-borne flavivirus Zika virus (ZIKV) is associated with neurological complications. Innate immunity is essential for the control of virus infection, but the innate immune mechanisms that impact viral infection of neurons remain poorly defined. Using the genetically tractable Drosophila system, we show that ZIKV infection of the adult fly brain leads to NF-kB-dependent inflammatory signaling, which serves to limit infection. ZIKV-dependent NF-kB activation induces the expression of Drosophila stimulator of interferon genes (dSTING) in the brain. dSTING protects against ZIKV by inducing autophagy in the brain. Loss of autophagy leads to increased ZIKV infection of the brain and death of the infected fly, while pharmacological activation of autophagy is protective. These data suggest an essential role for an inflammation-dependent STING pathway in the control of neuronal infection and a conserved role for STING in antimicrobial autophagy, which may represent an ancestral function for this essential innate immune sensor."
Recent related post:
http://flydiseasemodels.blogspot.com/2018/12/studies-in-drosophila-help-reveal-how.html
Abstract: "The emerging arthropod-borne flavivirus Zika virus (ZIKV) is associated with neurological complications. Innate immunity is essential for the control of virus infection, but the innate immune mechanisms that impact viral infection of neurons remain poorly defined. Using the genetically tractable Drosophila system, we show that ZIKV infection of the adult fly brain leads to NF-kB-dependent inflammatory signaling, which serves to limit infection. ZIKV-dependent NF-kB activation induces the expression of Drosophila stimulator of interferon genes (dSTING) in the brain. dSTING protects against ZIKV by inducing autophagy in the brain. Loss of autophagy leads to increased ZIKV infection of the brain and death of the infected fly, while pharmacological activation of autophagy is protective. These data suggest an essential role for an inflammation-dependent STING pathway in the control of neuronal infection and a conserved role for STING in antimicrobial autophagy, which may represent an ancestral function for this essential innate immune sensor."
Recent related post:
http://flydiseasemodels.blogspot.com/2018/12/studies-in-drosophila-help-reveal-how.html
Fly study explores molecular mechanisms of A-beta-induced pathology
Cheng KC, Chiang HC. XBP1 and PERK Have Distinct Roles in Aβ-Induced Pathology. Mol Neurobiol. 2018 Sep;55(9):7523-7532. doi:10.1007/s12035-018-0942-y. PMID: 29427089.
The abstract: "Endoplasmic reticulum (ER) stress triggers multiple cellular signals to restore cellular function or induce proapoptosis that is altered in the brains of patients with Alzheimer's disease (AD). However, the role of ER stress in β-amyloid (Aβ)-induced AD pathology remains elusive, and data obtained from different animal models and under different experimental conditions are sometimes controversial. The current study conducted in vivo genetic experiments to systematically examine the distinct role of each ER stress effector during disease progression. Our results indicated that inositol-requiring enzyme 1 was activated before protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation in Aβ42 transgenic flies. Proteasome activity played a key role in this sequential activation. Furthermore, our study separated learning deficits from early degeneration in Aβ-induced impairment by demonstrating that X-box binding protein 1 overexpression at an early stage reversed Aβ-induced early death without affecting learning performance in the Aβ42 transgenic flies. PERK activation was determined to only enhance Aβ-induced learning deficits. Moreover, proteasome overactivation was determined to delay PERK activation and improve learning deficits. Altogether, the findings of this study demonstrate the complex roles of ER stress during Aβ pathogenesis and the possibility of using different ER stress effectors as reporters to indicate the status of disease progression."
The abstract: "Endoplasmic reticulum (ER) stress triggers multiple cellular signals to restore cellular function or induce proapoptosis that is altered in the brains of patients with Alzheimer's disease (AD). However, the role of ER stress in β-amyloid (Aβ)-induced AD pathology remains elusive, and data obtained from different animal models and under different experimental conditions are sometimes controversial. The current study conducted in vivo genetic experiments to systematically examine the distinct role of each ER stress effector during disease progression. Our results indicated that inositol-requiring enzyme 1 was activated before protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation in Aβ42 transgenic flies. Proteasome activity played a key role in this sequential activation. Furthermore, our study separated learning deficits from early degeneration in Aβ-induced impairment by demonstrating that X-box binding protein 1 overexpression at an early stage reversed Aβ-induced early death without affecting learning performance in the Aβ42 transgenic flies. PERK activation was determined to only enhance Aβ-induced learning deficits. Moreover, proteasome overactivation was determined to delay PERK activation and improve learning deficits. Altogether, the findings of this study demonstrate the complex roles of ER stress during Aβ pathogenesis and the possibility of using different ER stress effectors as reporters to indicate the status of disease progression."
Friday, February 1, 2019
Drosophila as "integral tool" for neurodegenerative disease research and personalized medicine -- review article now available in PubMed Central
Deal SL, Yamamoto S. Unraveling Novel Mechanisms of Neurodegeneration Through a Large-Scale Forward Genetic Screen in Drosophila. Front Genet. 2019 Jan 14;9:700. PMID: 30693015; PMCID: PMC6339878.
The abstract: "Neurodegeneration is characterized by progressive loss of neurons. Genetic and environmental factors both contribute to demise of neurons, leading to diverse devastating cognitive and motor disorders, including Alzheimer's and Parkinson's diseases in humans. Over the past few decades, the fruit fly, Drosophila melanogaster, has become an integral tool to understand the molecular, cellular and genetic mechanisms underlying neurodegeneration. Extensive tools and sophisticated technologies allow Drosophila geneticists to identify and study evolutionarily conserved genes that are essential for neural maintenance. In this review, we will focus on a large-scale mosaic forward genetic screen on the fly X-chromosome that led to the identification of a number of essential genes that exhibit neurodegenerative phenotypes when mutated. Most genes identified from this screen are evolutionarily conserved and many have been linked to human diseases with neurological presentations. Systematic electrophysiological and ultrastructural characterization of mutant tissue in the context of the Drosophila visual system, followed by a series of experiments to understand the mechanism of neurodegeneration in each mutant led to the discovery of novel molecular pathways that are required for neuronal integrity. Defects in mitochondrial function, lipid and iron metabolism, protein trafficking and autophagy are recurrent themes, suggesting that insults that eventually lead to neurodegeneration may converge on a set of evolutionarily conserved cellular processes. Insights from these studies have contributed to our understanding of known neurodegenerative diseases such as Leigh syndrome and Friedreich's ataxia and have also led to the identification of new human diseases. By discovering new genes required for neural maintenance in flies and working with clinicians to identify patients with deleterious variants in the orthologous human genes, Drosophila biologists can play an active role in personalized medicine."
The abstract: "Neurodegeneration is characterized by progressive loss of neurons. Genetic and environmental factors both contribute to demise of neurons, leading to diverse devastating cognitive and motor disorders, including Alzheimer's and Parkinson's diseases in humans. Over the past few decades, the fruit fly, Drosophila melanogaster, has become an integral tool to understand the molecular, cellular and genetic mechanisms underlying neurodegeneration. Extensive tools and sophisticated technologies allow Drosophila geneticists to identify and study evolutionarily conserved genes that are essential for neural maintenance. In this review, we will focus on a large-scale mosaic forward genetic screen on the fly X-chromosome that led to the identification of a number of essential genes that exhibit neurodegenerative phenotypes when mutated. Most genes identified from this screen are evolutionarily conserved and many have been linked to human diseases with neurological presentations. Systematic electrophysiological and ultrastructural characterization of mutant tissue in the context of the Drosophila visual system, followed by a series of experiments to understand the mechanism of neurodegeneration in each mutant led to the discovery of novel molecular pathways that are required for neuronal integrity. Defects in mitochondrial function, lipid and iron metabolism, protein trafficking and autophagy are recurrent themes, suggesting that insults that eventually lead to neurodegeneration may converge on a set of evolutionarily conserved cellular processes. Insights from these studies have contributed to our understanding of known neurodegenerative diseases such as Leigh syndrome and Friedreich's ataxia and have also led to the identification of new human diseases. By discovering new genes required for neural maintenance in flies and working with clinicians to identify patients with deleterious variants in the orthologous human genes, Drosophila biologists can play an active role in personalized medicine."
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