Thursday, January 31, 2019

Opinion article suggests "fly models should figure prominently in the drug discovery pipeline"

Papanikolopoulou K, Mudher A, Skoulakis E. An assessment of the translational relevance of Drosophila in drug discovery. Expert Opin Drug Discov. 2019 Jan21:1-11. PMID: 30664368.

The abstract: "Drosophila melanogaster offers a powerful expedient and economical system with facile genetics. Because of the high sequence and functional conservation with human disease-associated genes, it has been cardinal in deciphering disease mechanisms at the genetic and molecular level. Drosophila are amenable to and respond well to pharmaceutical treatment which coupled to their genetic tractability has led to discovery, repositioning, and validation of a number of compounds. Areas covered: This review summarizes the generation of fly models of human diseases, their advantages and use in elucidation of human disease mechanisms. Representative studies provide examples of the utility of this system in modeling diseases and the discovery, repositioning and testing on pharmaceuticals to ameliorate them. Expert opinion: Drosophila offers a facile and economical whole animal system with many homologous organs to humans, high functional conservation and established methods of generating and validating human disease models. Nevertheless, it remains relatively underused as a drug discovery tool probably because its relevance to mammalian systems remains under question. However, recent exciting success stories using Drosophila disease models for drug screening, repositioning and validation strongly suggest that fly models should figure prominently in the drug discovery pipeline from bench to bedside."

Drosophila model of AD used to explore potential positive impact of ionizing radiation treatment

Hwang S, Jeong H, Hong EH, Joo HM, Cho KS, Nam SY. Low-dose ionizing radiation alleviates Aβ42-induced cell death via regulating AKT and p38 pathways in Drosophila Alzheimer's disease models. Biol Open. 2019 Jan 22. pii: bio.036657. PMID: 30670376.

From the abstract: "Ionizing radiation is widely used in medicine ... Here, we report that low-dose ionizing radiation has beneficial effects in human amyloid-β42 (Aβ42)-expressing Drosophila Alzheimer's disease (AD) models. ... In addition, overexpression of phosphatase and tensin homolog (PTEN), a negative regulator of the AKT signaling pathway, or a null mutant of AKT strongly suppressed the beneficial effects of low-dose ionizing radiation in Aβ42-expressing flies. These results indicate that low-dose ionizing radiation suppresses Aβ42-induced cell death through regulation of the AKT and p38 MAPK signaling pathways ..."

Fly models of metabolic disorders that induce seizures used to study potential positive impact of ketogenic diet

Fogle KJ, Smith AR, Satterfield SL, Gutierrez AC, Hertzler JI, McCardell CS, Shon JH, Barile ZJ, Novak MO, Palladino MJ. Ketogenic and anaplerotic dietary modifications ameliorate seizure activity in Drosophila models of mitochondrial encephalomyopathy and glycolytic enzymopathy. Mol Genet Metab. 2019 Jan 17. PMID: 30683556.

From the abstract: "Seizures are a feature not only of the many forms of epilepsy, but also of global metabolic diseases such as mitochondrial encephalomyopathy (ME) and glycolytic enzymopathy (GE). Modern anti-epileptic drugs (AEDs) are successful in many cases, but some patients are refractory to existing AEDs, which has led to a surge in interest in clinically managed dietary therapy such as the ketogenic diet (KD). This high-fat, low-carbohydrate diet causes a cellular switch from glycolysis to fatty acid oxidation and ketone body generation, ... We have recently shown that a Drosophila model of human ME (ATP61) responds robustly to the KD; here, we have investigated the mechanistic importance of the major metabolic consequences of the KD in the context of this bioenergetics disease: ketogenesis, reduction of glycolysis, and anaplerosis. ... Furthermore, our data reveal that multiple seizure models, in addition to ATP61, are treatable with the ketogenic diet. Importantly, one of these mutants is TPIsugarkill, which models human glycolytic enzymopathy, an incurable metabolic disorder ..."

Genetic screen in flies helps elucidate cellular mechanisms of spinocerebellar ataxia type 3 (SCA3)

Chen ZS, Wong AKY, Cheng TC, Koon AC, Chan HYE. FipoQ/FBXO33, a Cullin-1 based ubiquitin ligase complex component modulates ubiquitination and solubility of polyglutamine disease protein. J Neurochem. 2019 Jan 26. doi: 10.1111/jnc.14669. PubMed PMID: 30685895.

From the abstract: "Polyglutamine (polyQ) diseases describe a group of progressive neurodegenerative disorders ... To date, nine such diseases, including spinocerebellar ataxia type 3 (SCA3), have been reported. The formation of SDS-insoluble protein aggregates in neurons causes cellular dysfunctions, such as impairment of the ubiquitin-proteasome system (UPS), and contributes to polyQ pathologies. Recently, the E3 ubiquitin ligases, which govern substrate specificity of the UPS, have been implicated in polyQ pathogenesis. The Cullin (Cul) proteins are major components of Cullin-RING ubiquitin ligases (CRLs) complexes that are evolutionarily conserved in the Drosophila genome. In this study, we examined the effect of individual Culs on SCA3 pathogenesis ... We further performed a genetic modifier screen of the 19 Drosophila F-box genes, and identified F-box involved in polyQ pathogenesis (FipoQ) as a genetic modifier of SCA3 degeneration ... In the human SK-N-MC cell model, we identified F-box only protein 33 (FBXO33) exerts similar functions as FipoQ ... These findings will lead to a better understanding of the disease mechanism of SCA3, and provide insights on developing treatments against SCA3."

Wednesday, January 30, 2019

Study of neuroprotection by urate using fly model of ALS

Zhang C, Yang Y, Liang W, Wang T, Wang S, Wang X, Wang Y, Jiang H, Feng H. Neuroprotection by urate on the Mutant hSOD1-related Cellular and Drosophila Models of Amyotrophic Lateral Sclerosis: Implication for GSH synthesis via Activating Akt/GSK3β/Nrf2/GCLC Pathways. Brain Res Bull. 2019 Jan 25. pii: S0361-9230(18)30605-1. PMID: 30690059.

From the abstract
: "Oxidative stress has been considered as a principal mechanism of motor neuron death in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease which could be caused by dominant mutations in an antioxidant enzyme superoxide dismutase-1 (SOD1). The aim of the present study was to investigate the potential neuroprotective effects and mechanisms of urate, an important endogenous antioxidant and a biomarker of favorable ALS progression rates, in the mutant human SOD1-related cellular and Drosophila models of ALS. Our results showed that urate treatment provided neuroprotective effects as confirmed by enhanced survival, attenuated motor impairments, reduced oxidative damage and increased antioxidant defense in hSOD1-G85R-expressing Drosophila models of ALS. ... Overall, these results suggested that, in addition to its direct scavenging of ROS, urate markedly enhanced GSH expression by activating Akt/GSK3β/Nrf2/GCLC pathway, and thus offering neuroprotective effects on motor neurons against oxidative stress."

Fly model used in drug discovery study related to FTD and ALS (research report now available at PubMed Central)

Simone R, et al. G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo. EMBO Mol Med. 2018 Jan;10(1):22-31. doi: 10.15252/emmm.201707850. PubMed PMID: 29113975; PubMed Central PMCID: PMC5760849.

From the abstract: "Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. ... We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G-quadruplex RNA ... Furthermore, they also reduce dipeptide repeat proteins and improve survival in vivo, in GGGGCC repeat-expressing Drosophila ... These data provide proof of principle that targeting GGGGCC repeat G-quadruplexes has therapeutic potential."

Fly Model of Alexander disease points to relevance of mechanotransduction signaling (research report now available from PubMed Central)

Wang L, Xia J, Li J, Hagemann TL, Jones JR, Fraenkel E, Weitz DA, Zhang SC, Messing A, Feany MB. Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease. Nat Commun. 2018 May 15;9(1):1899. doi:10.1038/s41467-018-04269-7. PubMed PMID: 29765022; PubMed Central PMCID: PMC5954157.

From the abstract
: "... Here we use models of Alexander disease, a severe brain disorder caused by gain-of-function mutations in GFAP, to demonstrate that misregulation of GFAP leads to activation of a mechanosensitive signaling cascade characterized by activation of the Hippo pathway and consequent increased expression of A-type lamin. Importantly, we use genetics to verify a functional role for dysregulated mechanotransduction signaling in promoting behavioral abnormalities and non-cell autonomous neurodegeneration. ... Our findings implicate altered mechanotransduction signaling as a key pathological cascade driving neuronal dysfunction and neurodegeneration in Alexander disease, and possibly also in other brain disorders characterized by gliosis."