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."
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