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. ..."

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."

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."

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."

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."

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."