Tuesday, October 31, 2017

Studies in flies and mice implicate glycation in neurodegenerative disease-associated protein toxicity

Vicente Miranda H, Szego ÉM, Oliveira LMA, Breda C, Darendelioglu E, de Oliveira RM, Ferreira DG, Gomes MA, Rott R, Oliveira M, Munari F, Enguita FJ,Simões T, Rodrigues EF, Heinrich M, Martins IC, Zamolo I, Riess O, Cordeiro C, Ponces-Freire A, Lashuel HA, Santos NC, Lopes LV, Xiang W, Jovin TM, Penque D, Engelender S, Zweckstetter M, Klucken J, Giorgini F, Quintas A, Outeiro TF. Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies. Brain. 2017 May 1;140(5):1399-1419. PMID: 28398476.

From the abstract: "α-Synuclein misfolding and aggregation is a hallmark in Parkinson's disease and in several other neurodegenerative diseases known as synucleinopathies. ... Combining molecular genetics with target-based approaches, we established that glycation, an unavoidable age-associated post-translational modification, enhanced α-synuclein toxicity in vitro and in vivo, in Drosophila and in mice. ... Altogether, our study demonstrates glycation constitutes a novel drug target that can be explored in synucleinopathies as well as in other neurodegenerative conditions."

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.