Sheik Mohideen S, Yamasaki Y, Omata Y, Tsuda L, Yoshiike Y. Nontoxic singlet oxygen generator as a therapeutic candidate for treating tauopathies. Sci Rep. 2015 Jun 1;5:10821. PMID: 26027742; PMCID: PMC4450544.
From the abstract: "Methylene blue (MB) inhibits the aggregation of tau, a main constituent
of neurofibrillary tangles. However, MB's mode of action in vivo is not
fully understood. MB treatment reduced the amount of sarkosyl-insoluble
tau in Drosophila that express human wild-type tau. MB concurrently
ameliorated the climbing deficits of transgenic tau flies to a limited
extent and diminished the climbing activity of wild-type flies. MB also
decreased the survival rate of wild-type flies. Based on its
photosensitive efficacies, we surmised that singlet oxygen generated
through MB under light might contribute to both the beneficial and toxic
effects of MB in vivo. ...
Our findings indicate that singlet oxygen generators with little
toxicity may be suitable drug candidates for treating tauopathies."
Wednesday, June 24, 2015
Monday, June 22, 2015
Review--fly models and intellectual disability
Androschuk A, Al-Jabri B, Bolduc FV. From Learning to Memory: What Flies Can Tell Us about Intellectual Disability Treatment. Front Psychiatry. 2015 Jun 3;6:85. PMID: 26089803; PMCID: PMC4453272.
From the abstract: "Intellectual disability (ID) ... affects 3% of the population and remains without pharmacological treatment. ... several model organisms have proven valuable in developing and screening candidate drugs. One such model organism is the fruit fly Drosophila. First, we review the current understanding of memory in human and its model in Drosophila. Second, we describe key signaling pathways involved ... Third, we characterize the types of memory defects found in patients with ID. Finally, we discuss how important insights gained from Drosophila learning and memory could be translated in clinical research to lead to better treatment development. "
From the abstract: "Intellectual disability (ID) ... affects 3% of the population and remains without pharmacological treatment. ... several model organisms have proven valuable in developing and screening candidate drugs. One such model organism is the fruit fly Drosophila. First, we review the current understanding of memory in human and its model in Drosophila. Second, we describe key signaling pathways involved ... Third, we characterize the types of memory defects found in patients with ID. Finally, we discuss how important insights gained from Drosophila learning and memory could be translated in clinical research to lead to better treatment development. "
Autophagy, retinopathy and the fly eye
Lőrincz P, Takáts S, Kárpáti M, Juhász G. iFly: The eye of the fruit fly as a model to study autophagy and related trafficking pathways. Exp Eye Res. 2015 Jun 16. pii: S0014-4835(15)00201-8. PMID: 26091788.
From the abstract: "Autophagy is a process by which eukaryotic cells degrade and recycle their intracellular components within lysosomes. Autophagy is induced by starvation to ensure survival of individual cells, and it has evolved to fulfill numerous additional roles in animals. ... Here we summarize the current knowledge of autophagy and related trafficking pathways in a convenient model: the compound eye of the fruit fly Drosophila melanogaster. In our review, we present a general introduction of the development and structure of the compound eye. This is followed by a discussion of various neurodegeneration models including retinopathies, with special emphasis on the protective role of autophagy against these diseases."
From the abstract: "Autophagy is a process by which eukaryotic cells degrade and recycle their intracellular components within lysosomes. Autophagy is induced by starvation to ensure survival of individual cells, and it has evolved to fulfill numerous additional roles in animals. ... Here we summarize the current knowledge of autophagy and related trafficking pathways in a convenient model: the compound eye of the fruit fly Drosophila melanogaster. In our review, we present a general introduction of the development and structure of the compound eye. This is followed by a discussion of various neurodegeneration models including retinopathies, with special emphasis on the protective role of autophagy against these diseases."
Aiming to help kids who undergo radiation therapy--fly as a model of radiation exposure
Sudmeier LJ, Howard SP, Ganetzky B. A Drosophila model to investigate the neurotoxic side effects of radiation exposure. Dis Model Mech. 2015 Jul 1;8(7):669-77. doi: 10.1242/dmm.019786. PMID: 26092528.
From the abstract: "Children undergoing cranial radiation therapy (CRT) for pediatric central nervous system malignancies are at increased risk for neurological deficits later in life. We have developed a model of neurotoxic damage in adult Drosophila following irradiation during the juvenile stages with the goal of elucidating underlying neuropathological mechanisms and of ultimately identifying potential therapeutic targets. ... This work demonstrates the usefulness of Drosophila to model the toxic effects of radiation during development, and has the potential to unravel underlying mechanisms and to facilitate the discovery of novel therapeutic interventions."
From the abstract: "Children undergoing cranial radiation therapy (CRT) for pediatric central nervous system malignancies are at increased risk for neurological deficits later in life. We have developed a model of neurotoxic damage in adult Drosophila following irradiation during the juvenile stages with the goal of elucidating underlying neuropathological mechanisms and of ultimately identifying potential therapeutic targets. ... This work demonstrates the usefulness of Drosophila to model the toxic effects of radiation during development, and has the potential to unravel underlying mechanisms and to facilitate the discovery of novel therapeutic interventions."
New fly model related to myotonic dystrophy type 1 (DM1)
Bargiela A, Cerro-Herreros E, Fernandez-Costa JM, Vilchez JJ, Llamusi B, Artero R. Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model. Dis Model Mech. 2015 Jul 1;8(7):679-90. PMID: 26092529.
From the abstract: "Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. ... results were validated in skeletal muscle biopsies from DM1 patients ... and also in DM1 myoblasts ... These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis."
From the abstract: "Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. ... results were validated in skeletal muscle biopsies from DM1 patients ... and also in DM1 myoblasts ... These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis."
Alzheimer's Disease and Polyphenols--review summarizes results from fly models
Jimenez-Del-Rio M, Velez-Pardo C. Alzheimer's Disease, Drosophila melanogaster and Polyphenols. Adv Exp Med Biol. 2015;863:21-53. PubMed PMID: 26092625.
From the abstract: "Alzheimer's disease (AD) is an insidious neurological disorder that affects memory, one of the human brain's main cognitive functions. Around 5.2 million Americans currently have AD, and the number threatens to climb to 7 million by 2020. Our native country, Colombia, is no exception with an estimated 260,000 individuals to be affected by AD in 2020. ... Drosophila melanogaster is increasingly being used as a valid in vivo model of AD. Here, we summarise data published within the past 16 years (1998-2014) on the molecular biology of AD and the use of polyphenols in the fly to understand the molecular actions and feasibility of these compounds in the treatment of AD."
From the abstract: "Alzheimer's disease (AD) is an insidious neurological disorder that affects memory, one of the human brain's main cognitive functions. Around 5.2 million Americans currently have AD, and the number threatens to climb to 7 million by 2020. Our native country, Colombia, is no exception with an estimated 260,000 individuals to be affected by AD in 2020. ... Drosophila melanogaster is increasingly being used as a valid in vivo model of AD. Here, we summarise data published within the past 16 years (1998-2014) on the molecular biology of AD and the use of polyphenols in the fly to understand the molecular actions and feasibility of these compounds in the treatment of AD."
Friday, June 19, 2015
Using SOS1 to neutralize KRAS -- fly studies contribute to characterization of new potential cancer therapeutic strategy
Leshchiner ES, Parkhitko A, Bird GH, Luccarelli J, Bellairs JA, Escudero S, Opoku-Nsiah K, Godes M, Perrimon N, Walensky LD. Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1761-6. PMID: 25624485; PMCID: PMC4330742.
From the abstract: "Activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) underlie the pathogenesis and chemoresistance of ∼ 30% of all human tumors, yet the development of high-affinity inhibitors that target the broad range of KRAS mutants remains a formidable challenge. Here, we report the development and validation of stabilized alpha helices of son of sevenless 1 (SAH-SOS1) as prototype therapeutics that directly inhibit wild-type and mutant forms of KRAS. ... The mechanism of action of SAH-SOS1 peptides was demonstrated by sequence-specific down-regulation of the ERK-MAP kinase phosphosignaling cascade in KRAS-driven cancer cells and in a Drosophila melanogaster model of Ras85D(V12) activation. These studies provide evidence for the potential utility of SAH-SOS1 peptides in neutralizing oncogenic KRAS in human cancer."
From the abstract: "Activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) underlie the pathogenesis and chemoresistance of ∼ 30% of all human tumors, yet the development of high-affinity inhibitors that target the broad range of KRAS mutants remains a formidable challenge. Here, we report the development and validation of stabilized alpha helices of son of sevenless 1 (SAH-SOS1) as prototype therapeutics that directly inhibit wild-type and mutant forms of KRAS. ... The mechanism of action of SAH-SOS1 peptides was demonstrated by sequence-specific down-regulation of the ERK-MAP kinase phosphosignaling cascade in KRAS-driven cancer cells and in a Drosophila melanogaster model of Ras85D(V12) activation. These studies provide evidence for the potential utility of SAH-SOS1 peptides in neutralizing oncogenic KRAS in human cancer."
Vinculin involvement in regulation of heart function during aging
Kaushik G, Spenlehauer A, Sessions AO, Trujillo AS, Fuhrmann A, Fu Z, Venkatraman V, Pohl D, Tuler J, Wang M, Lakatta EG, Ocorr K, Bodmer R, Bernstein SI, Van Eyk JE, Cammarato A, Engler AJ. Vinculin network-mediated cytoskeletal remodeling regulates contractile function in the aging heart. Sci Transl Med. 2015 Jun 17;7(292):292ra99. PMID: 26084806.
From the abstract: "The human heart is capable of functioning for decades despite minimal cell turnover or regeneration, suggesting that molecular alterations help sustain heart function with age. However, identification of compensatory remodeling events in the aging heart remains elusive. We present the cardiac proteomes of young and old rhesus monkeys and rats, from which we show that certain age-associated remodeling events within the cardiomyocyte cytoskeleton are highly conserved and beneficial rather than deleterious. Targeted transcriptomic analysis in Drosophila confirmed conservation and implicated vinculin as a unique molecular regulator of cardiac function during aging. ... Moreover, cardiac-specific vinculin overexpression increased median life span by more than 150% in flies. ... These findings suggest that the heart has molecular mechanisms to sustain performance and promote longevity, which may be assisted by therapeutic intervention to ameliorate the decline of function in aging patient hearts."
From the abstract: "The human heart is capable of functioning for decades despite minimal cell turnover or regeneration, suggesting that molecular alterations help sustain heart function with age. However, identification of compensatory remodeling events in the aging heart remains elusive. We present the cardiac proteomes of young and old rhesus monkeys and rats, from which we show that certain age-associated remodeling events within the cardiomyocyte cytoskeleton are highly conserved and beneficial rather than deleterious. Targeted transcriptomic analysis in Drosophila confirmed conservation and implicated vinculin as a unique molecular regulator of cardiac function during aging. ... Moreover, cardiac-specific vinculin overexpression increased median life span by more than 150% in flies. ... These findings suggest that the heart has molecular mechanisms to sustain performance and promote longevity, which may be assisted by therapeutic intervention to ameliorate the decline of function in aging patient hearts."
Thursday, June 18, 2015
Automated fly climbing assay used to uncover loci with links to A-beta-42
Liu H, Han M, Li Q, Zhang X, Wang WA, Huang F. Automated rapid iterative negative geotaxis assay and its use in a genetic screen for modifiers of Aβ(42)-induced locomotor decline in Drosophila. Neurosci Bull. 2015 Jun 15. PMID: 26077703.
From the abstract: "The negative-geotaxis climbing assay is used to efficiently study aging and neurodegeneration in Drosophila. To make it suitable for large-scale study, a method ... has been established by simultaneously photographing the climbing of multiple groups of flies when they are manually tapped down in test tubes. Here, we automated the assay by using a well-controlled electric motor to drive the tapping, and a homemade program to analyze the climbing height of flies. ... we examined the effect of third chromosome deficiencies on the accelerated locomotor decline in Aβ42-expressing flies, and isolated 7 suppressors and 15 enhancers."
From the abstract: "The negative-geotaxis climbing assay is used to efficiently study aging and neurodegeneration in Drosophila. To make it suitable for large-scale study, a method ... has been established by simultaneously photographing the climbing of multiple groups of flies when they are manually tapped down in test tubes. Here, we automated the assay by using a well-controlled electric motor to drive the tapping, and a homemade program to analyze the climbing height of flies. ... we examined the effect of third chromosome deficiencies on the accelerated locomotor decline in Aβ42-expressing flies, and isolated 7 suppressors and 15 enhancers."
Wednesday, June 17, 2015
Fly study results suggest limitations to usefulness of a potential treatment for mitochondrial disorders
Kemppainen KK, Kemppainen E, Jacobs HT. The alternative oxidase AOX does not rescue the phenotype of tko25t mutant flies. G3 (Bethesda). 2014 Aug 21;4(10):2013-21. PMID: 25147191; PMCID: PMC4199707.
From the abstract: "A point mutation [technical knockout(25t) (tko(25t))] in the Drosophila gene coding for mitoribosomal protein S12 generates a phenotype of developmental delay and bang sensitivity. tko(25t) has been intensively studied as an animal model for human mitochondrial diseases ... Transgenic expression in Drosophila of the alternative oxidase (AOX) derived from Ciona intestinalis has previously been shown to mitigate the toxicity of respiratory chain inhibitors and to rescue mutant and knockdown phenotypes ... We therefore tested whether AOX expression could compensate the mutant phenotype of tko(25t) ... We conclude that AOX does not rescue tko(25t) and that the mutant phenotype is not solely due to limitations on electron flow in the respiratory chain, but rather to a more complex metabolic defect. The future therapeutic use of AOX in disorders of mitochondrial translation may thus be of limited value."
From the abstract: "A point mutation [technical knockout(25t) (tko(25t))] in the Drosophila gene coding for mitoribosomal protein S12 generates a phenotype of developmental delay and bang sensitivity. tko(25t) has been intensively studied as an animal model for human mitochondrial diseases ... Transgenic expression in Drosophila of the alternative oxidase (AOX) derived from Ciona intestinalis has previously been shown to mitigate the toxicity of respiratory chain inhibitors and to rescue mutant and knockdown phenotypes ... We therefore tested whether AOX expression could compensate the mutant phenotype of tko(25t) ... We conclude that AOX does not rescue tko(25t) and that the mutant phenotype is not solely due to limitations on electron flow in the respiratory chain, but rather to a more complex metabolic defect. The future therapeutic use of AOX in disorders of mitochondrial translation may thus be of limited value."
Monday, June 15, 2015
Studies use multiple fly models to investigate links between iron and A-beta
Ott S, Dziadulewicz N, Crowther DC. Iron is a specific cofactor for distinct oxidation- and aggregation-dependent Aβ toxicity mechanisms. Dis Model Mech. 2015 Apr 23. pii: dmm.019042. PMID: 26035384.
From the abstract: "Metals including iron are present at high concentrations in amyloid plaques in patients with Alzheimer's disease where they are also thought to be co-factors in generating oxidative stress and modulating amyloid formation. In this study we present data from several Drosophila models of neurodegenerative proteinopathies indicating that the interaction between iron and Aβ is specific and is not seen for other aggregation-prone polypeptides. ... Understanding how Aβ mediates neurotoxic effects in vivo will help us better target pathological pathways using aggregation-blockers and metal-modifying agents."
From the abstract: "Metals including iron are present at high concentrations in amyloid plaques in patients with Alzheimer's disease where they are also thought to be co-factors in generating oxidative stress and modulating amyloid formation. In this study we present data from several Drosophila models of neurodegenerative proteinopathies indicating that the interaction between iron and Aβ is specific and is not seen for other aggregation-prone polypeptides. ... Understanding how Aβ mediates neurotoxic effects in vivo will help us better target pathological pathways using aggregation-blockers and metal-modifying agents."
Wednesday, June 3, 2015
Review looks at contributions of Drosophila research related to Fragile X syndrome and discusses discordance
Weisz ED, Monyak RE, Jongens TA. Deciphering Discord: How Drosophila research has enhanced our understanding of the importance of FMRP in different spatial and temporal contexts. Exp Neurol. 2015 May 27. pii: S0014-4886(15)30001-7. PMID: 26026973.
From the abstract: "Fragile X Syndrome (FXS) is the most common heritable form of intellectual impairment as well as the leading monogenetic cause of autism. ... Research efforts in Drosophila melanogaster have revealed key insights into the mechanistic underpinnings of FXS. While much remains unknown, it is increasingly apparent that FXS involves a myriad of spatial and temporally specific alterations in cellular function. Consequently, the literature is filled with numerous discordant findings. Researchers and clinicians alike must be cognizant of this dissonance, as it will likely be important for the design of preclinical studies to assess the efficacy of therapeutic strategies to improve the lives of FXS patients."
From the abstract: "Fragile X Syndrome (FXS) is the most common heritable form of intellectual impairment as well as the leading monogenetic cause of autism. ... Research efforts in Drosophila melanogaster have revealed key insights into the mechanistic underpinnings of FXS. While much remains unknown, it is increasingly apparent that FXS involves a myriad of spatial and temporally specific alterations in cellular function. Consequently, the literature is filled with numerous discordant findings. Researchers and clinicians alike must be cognizant of this dissonance, as it will likely be important for the design of preclinical studies to assess the efficacy of therapeutic strategies to improve the lives of FXS patients."
New fly model related to mitochondrial diseases
Holmbeck MA, Donner JR, Villa-Cuesta E, Rand DM. A Drosophila model for mito-nuclear diseases generated by an incompatible tRNA-tRNA synthetase interaction. Dis Model Mech. 2015 May 5. pii: dmm.019323. PMID: 26035388.
From the abstract: "... Because mutations in mitochondrial tRNATyr are associated with exercise intolerance in humans, this mitochondrial-nuclear introgression model in Drosophila provides a means to dissect the molecular basis of these, and other mitochondrial diseases that are a consequence of the joint genetic architecture of mitochondrial function."
From the abstract: "... Because mutations in mitochondrial tRNATyr are associated with exercise intolerance in humans, this mitochondrial-nuclear introgression model in Drosophila provides a means to dissect the molecular basis of these, and other mitochondrial diseases that are a consequence of the joint genetic architecture of mitochondrial function."
Fly study related to Parkinson's disease places Clu in context of PINK1, Parkin and mitochondrial quality control
Sen A, Kalvakuri S, Bodmer R, Cox RT. Clueless, a protein required for mitochondrial function, interacts with the PINK1-Parkin complex in Drosophila. Dis Model Mech. 2015 Jun 1;8(6):577-589. PMID: 26035866.
From the abstract: "Loss of mitochondrial function often leads to neurodegeneration and is thought to be one of the underlying causes ... we show that clu also genetically interacts with PINK1, and our epistasis analysis places clu downstream of PINK1 and upstream of park. ... Clu forms a complex with PINK1 and Park ... Lack of Clu causes PINK1 and Park to interact with each other, and clu mutants have decreased mitochondrial protein levels ... these results suggest that Clu directly modulates mitochondrial function, and that Clu's function contributes to the PINK1-Park pathway of mitochondrial quality control."
Note: clu has been conserved--the orthologous human protein appears to be CLUH.
From the abstract: "Loss of mitochondrial function often leads to neurodegeneration and is thought to be one of the underlying causes ... we show that clu also genetically interacts with PINK1, and our epistasis analysis places clu downstream of PINK1 and upstream of park. ... Clu forms a complex with PINK1 and Park ... Lack of Clu causes PINK1 and Park to interact with each other, and clu mutants have decreased mitochondrial protein levels ... these results suggest that Clu directly modulates mitochondrial function, and that Clu's function contributes to the PINK1-Park pathway of mitochondrial quality control."
Note: clu has been conserved--the orthologous human protein appears to be CLUH.
Review--modeling Alzheimers disease in flies
Fernandez-Funez P, de Mena L, Rincon-Limas DE. Modeling the complex pathology of Alzheimer's disease in Drosophila. Exp Neurol. 2015 May 27. pii: S0014-4886(15)00169-7. PMID: 26024860.
New fly model related to Adult T-cell leukemia/lymphoma (ATLL)
Shirinian M, Kambris Z, Hamadeh L, Grabbe C, Journo C, Mahieux R, Bazarbachi A. A transgenic Drosophila melanogaster model to study Human T-Lymphotropic Virus oncoprotein Tax-1-driven transformation in vivo. J Virol. 2015 May 20. pii: JVI.00918-15. PMID: 25995252.
From the abstract: "HTLV-1-induced adult T-cell leukemia/lymphoma is an aggressive malignancy. ... We describe transgenic Drosophila models expressing Tax in the compound eye and plasmatocytes. ... Tax-1 but not Tax-2 induces ommatidia perturbation and increased plasmatocyte proliferation ... validating this new in vivo model."
From the abstract: "HTLV-1-induced adult T-cell leukemia/lymphoma is an aggressive malignancy. ... We describe transgenic Drosophila models expressing Tax in the compound eye and plasmatocytes. ... Tax-1 but not Tax-2 induces ommatidia perturbation and increased plasmatocyte proliferation ... validating this new in vivo model."
Fly study suggest links between mitochondrial iron transport and Friedreich's ataxia
Navarro JA, Botella JA, Metzendorf C, Lind MI, Schneuwly S. Mitoferrin modulates iron toxicity in a Drosophila model of Friedreich׳s ataxia. Free Radic Biol Med. 2015 Apr 2. pii: S0891-5849(15)00126-4. PMID: 25841783.
From the abstract: "Friedreich׳s ataxia is the most important recessive ataxia in the Caucasian population. Loss of frataxin expression affects the production of iron-sulfur clusters and, therefore, mitochondrial energy production. One of the pathological consequences is an increase of iron transport into the mitochondrial compartment leading to a toxic accumulation of reactive iron. ... frataxin-deficient flies were hypersensitive toward dietary iron and developed an iron-dependent decay of mitochondrial functions. ... mitoferrin downregulation improved many of the frataxin-deficient conditions ... whereas mitoferrin overexpression exacerbated most of them. ... demonstrates the crucial role of mitoferrin dysfunction in the etiology of Friedreich׳s ataxia and provides evidence that impairment of mitochondrial iron transport could be an effective treatment of the disease."
From the abstract: "Friedreich׳s ataxia is the most important recessive ataxia in the Caucasian population. Loss of frataxin expression affects the production of iron-sulfur clusters and, therefore, mitochondrial energy production. One of the pathological consequences is an increase of iron transport into the mitochondrial compartment leading to a toxic accumulation of reactive iron. ... frataxin-deficient flies were hypersensitive toward dietary iron and developed an iron-dependent decay of mitochondrial functions. ... mitoferrin downregulation improved many of the frataxin-deficient conditions ... whereas mitoferrin overexpression exacerbated most of them. ... demonstrates the crucial role of mitoferrin dysfunction in the etiology of Friedreich׳s ataxia and provides evidence that impairment of mitochondrial iron transport could be an effective treatment of the disease."
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