Friday, August 31, 2012

Phosphate toxicity and lifespan. Recent review.

This review describes how Drosophila can be used to model dietary phosphate toxicity or hyperphosphatemia, an imbalance that can be associated with chronic kidney disease.

Bergwitz, C. Dietary phosphate modifies lifespan in Drosophila. Nephrol. Dial. Transplant. (2012) 27(9): 3399-3406 . PubMed ID: 22942172

Resource for disease information: GeneReviews.

The NCBI Bookshelf includes GeneReviews, which has detailed information about many human diseases, including information about relevant genes. Another resource to check out if you're looking to dive deep into a particular disease and focus fly research in disease-relevant directions. See links for more.

Drosophila models of deafness. Foundational report.

This paper describes a large-scale effort to further develop Drosophila as a model for study of hearing and hearing-related diseases.

Pingkalai R. Senthilan, David Piepenbrock, Guvanch Ovezmyradov, Björn Nadrowski, Susanne Bechstedt, Stephanie Pauls, Margret Winkler, Wiebke Möbius, Jonathon Howard, Martin C. Göpfert. Drosophila Auditory Organ Genes and Genetic Hearing Defects. Cell 31 August 2012 (Vol. 150, Issue 5, pp. 1042-1054).

The study includes but is not limited to comparative mRNA analysis to identify relevant transcripts; in situ hybridization to visualize transcripts in a relevant organ; and characterization of auditory phenotypes. A Cell 'Preview' article by Lewis & Steel is also available. These authors describe the study by Senthilan et al. as providing "a new resource to aid identification of genes involved in deafness."

Wednesday, August 29, 2012

GWAS suggests role for KCNJ2 in thyrotoxic periodic paralysis.

This GWAS-identified human gene has a fly ortholog, too? Yes, it seems so.

Cheung CL, Lau KS, Ho AY, Lee KK, Tiu SC, Lau EY, Leung J, Tsang MW, Chan KW, Yeung CY, Woo YC, Cheung EY, Hung VH, Pang HK, Hung CS, Sham PC, Kung AW. Genome-wide association study identifies a susceptibility locus for thyrotoxic periodic paralysis at 17q24.3. Nat Genet. 2012 Aug 5. doi: 10.1038/ng.2367. PubMed PMID: 22863731

The top-scoring Drosophila DIOPT result for human KCNJ2 is Irk2
Other related genes include Ir and Irk3.

The Gal4-UAS system could be used to test RNAi knockdown of these genes, as the FlyBase reports (click gene links above) show that RNAi fly stocks from the Transgenic RNAi Project (TRiP) and Vienna Drosophila RNAi Center (VDRC) exist for these genes.

According to Wikipedia, thyrotoxic periodic paralysis is classified under the larger umbrella of channelopathies, which also include alternating hemiplegia of childhood.

GWAS implicates ATP1A3 in alternating hemiplegia of childhood.

A genome-wide association study points to mutations in the human gene ATP1A3 as causative in alternating hemiplegia of childhood (AHC). The authors state that distinct mutations in same gene has been implicated in rapid-onset dystonia-parkinsonism.

Heinzen EL, Swoboda KJ, Hitomi Y, Gurrieri F, Nicole S, et al. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet. 2012 Jul 29. doi:10.1038/ng.2358. PubMed PMID: 22842232.

The fly ortholog of ATP1A3 appears to be ATPalpha (FBgn0002921) (DIOPT score = 8, indicating that 8 of 9 published ortholog prediction algorithms/tools predict this human-fly gene relationship).

As annotated in FlyBase, researchers have isolated a large number of mutations in ATPalpha and mutant phenotypes include lethality, the 'bang sensitive' phenotype, hypoactivity, paralysis and neurophysiological defects. Presumably these existing fly models could be used to study AHC.

GWAS implicates NMNAT1 in Leber congential amaurosis.

Two reports in the recent issue of Nature Genetics implicate the human gene NMNAT1 in Leber congenital amaurosis, rare inherited eye disease.

Chiang PW, Wang J, Chen Y, Fu Q, Zhong J, Chen Y, Yi X, Wu R, Gan H, Shi Y, Chen Y, Barnett C, Wheaton D, Day M, Sutherland J, Heon E, Weleber RG, Gabriel LA, Cong P, Chuang K, Ye S, Sallum JM, Qi M. Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis. Nat Genet. 2012 Jul 29. doi:10.1038/ng.2370. PubMed PMID: 22842231.

Koenekoop RK, Wang H, Majewski J, Wang X, Lopez I, Ren H, Chen Y, Li Y, Fishman GA, Genead M, Schwartzentruber J, Solanki N, Traboulsi EI, Cheng J, Logan CV, McKibbin M, Hayward BE, Parry DA, Johnson CA, Nageeb M; Finding of Rare Disease Genes (FORGE) Canada Consortium, Poulter JA, Mohamed MD, Jafri H, Rashid Y, Taylor GR, Keser V, Mardon G, Xu H, Inglehearn CF, Fu Q, Toomes C, Chen R. Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. Nat Genet. 2012 Jul 29. doi: 10.1038/ng.2356. PubMed PMID: 22842230.

The fly ortholog of NMNAT1 is Nmnat (for Nicotinamide mononucleotide adenylyltransferase). As annotated in FlyBase, phenotypes observed for mutations in Drosophila Nmnat include phenotypes associated with the eye.

More info on the human genetics of Leber congential amaurosis is available here.

Signal-mediated growth control and mitochondria. Recent report.

This recent report links mitochondrial fusion and cancer-relevant, signal-mediated growth control by the hippo signal transduction pathway. 

A link to mitochondria sounds familiar? Mitochondrial dynamics were recently linked to neurodegenerative disease as well--see this post.

Nagaraj R, Gururaja-Rao S, Jones KT, Slattery M, Negre N, Braas D, Christofk H, White KP, Mann R, Banerjee U. Control of mitochondrial structure and function by the Yorkie/YAP oncogenic pathway. Genes Dev. 2012 Aug 27. PubMed PMID: 22925885

The hippo signaling pathway has its own Wikipedia page. And as of this posting, it's been nominated but not yet created as a pathway at WikiPathways.

Tuesday, August 28, 2012

Brain disease and fly models. Foundational review.

This review touches on a number of neurological and neuromuscular degenerative diseases, metabolic disorders, tumors, epilepsy and trauma (injury and regeneration).

Jeibmann & Paulus (2009) Drosophila melanogaster as a model organism of brain diseases. Int J Mol Sci. 2009 Feb;10(2):407-40. PubMed: 19333415; PubMed Central: PMC2660653.

Molecular chaperones and ALS. Recent Report.

This open access paper describes use of a fly model of amyotrophic lateral sclerosis (ALS), which is also known as Lou Gehrig's disease, to link protein aggregation to neurotoxicity.

Gregory JM, Barros TP, Meehan S, Dobson CM, Luheshi LM. The aggregation and neurotoxicity of TDP-43 and its ALS-associated 25 kDa fragment are differentially affected by molecular chaperones in Drosophila. PLoS One. 2012;7(2):e31899. PubMed PMID: 22384095; PubMed Central PMCID: PMC3284513.

Flies used in the study include transgenic animals in which the Gal4-UAS system was used to express HA-tagged TDP-43.

See also the Bloomington Drosophila Stock Center's page on ALS-related fly stocks

A search with "amyotrophic lateral sclerosis" (without the quotes) entered into the box "Or disease full text search" at DIOPT-DIST brings up more than 100 results.

This YouTube video (unrelated to the article cited above) shows a comparison of flies mutant for an ALS-related gene ortholog with normal flies in the "climbing assay," a simple assay of motor control.  After a quick tap of the vial, normal flies will reorient themselves and crawl to the top of the vial.

Mitochondria and neurodegeneration. Recent Report.

A breaking report newly implicates mitochondrial dynamics in neurodegenerative disease.

Duboff B, Götz J, Feany MB. Tau Promotes Neurodegeneration via DRP1 Mislocalization In Vivo. Neuron. 2012 Aug 23;75(4):618-32. PubMed PMID: 22920254

Fly model used (from the Materials and Methods): "Our Drosophila model of tauopathy is based on expression of either wild-type or FTDP-17 linked mutant forms of tau in neurons using the UAS/GAL4 bipartite expression system (Brand and Perrimon, 1993) and a panneuronal driver (elav-GAL4). In these studies, we predominantly express human tau carrying the R406W mutation ... To examine mitochondrial morphology in our model, we coexpressed tau with mitochondrially localized GFP (mitoGFP) in neurons of the adult brain."

Update: this review article looks relevant: Itoh K, Nakamura K, Iijima M, Sesaki H. Mitochondrial dynamics in neurodegeneration. Trends Cell Biol. 2013 Feb;23(2):64-71. PMID: 23159640; PMCID: PMC3558617.

Monday, August 27, 2012

Fly seizure models and drug resistance. Recent report.

Bao GS, Wang WA, Wang TZ, Huang JK, He H, Liu Z, Huang FD. Overexpression of human MRP1 in neurons causes resistance to antiepileptic drugs in Drosophila seizure mutants. J Neurogenet. 2011 Dec;25(4):201-6. Epub 2011 Oct 25. PubMed PMID: 22026728

Seizure model used: flies carrying a mutation in bang senseless, which has the official FlyBase name paralytic and the FlyBase ID FBgn0264255.

Diacylglycerol kinase and Huntingtin toxicity. Recent report.

Zhang N, Li B, Al-Ramahi I, Cong X, Held JM, Kim E, Botas J, Gibson BW, Ellerby LM. Inhibition of lipid signaling enzyme diacylglycerol kinase epsilon attenuates mutant huntingtin toxicity. J Biol Chem. 2012 Jun 15;287(25):21204-13. PubMed PMID: 22511757; PubMed Central PMCID: PMC3375542.

The fly model used in the study (from their Materials and Methods section):  "The nervous system driver line elav-GALc155 was obtained from the Bloomington Drosophila Stock Center at University of Indiana. The inducible shRNA line targeting the Drosophila homolog of DGKϵ (4659GD) was obtained from the Vienna Drosophila RNAi Center."

Related resources: BDSC's page on Huntington's Disease-related fly stocks.
See also posts on DK deficiency.
See also all posts on Huntingtons disease.

Drosophila models. Recent review.

This paper would be a good starting point if you're new to thinking about fly models of disease. Includes figures describing some of the basic approaches and methods.

Chen KF, Crowther DC. Functional genomics in Drosophila models of human disease. Brief Funct Genomics. 2012 Aug 22. PubMed PMID: 22914042.

Tuesday, August 21, 2012

Glycerol Kinase Deficiency Model. Recent Report.

Mutations in eye pigmentation genes were among the first identified in Drosophila and helped contribute to our understanding of general mechanisms of genetic inheritance. Now they're impacting our understanding of a human disease model. In the recent report cited below, the authors describe development of a fly model of glycerol kinase deficiency and subsequent analysis of the affected flies.

Open access paper.

New Fly Model:  Glycerol kinase deficiency.

Wightman PJ, Jackson GR, Dipple KM. Glycerol hypersensitivity in a Drosophila model for glycerol kinase deficiency is affected by mutations in eye pigmentation genes. PLoS One. 2012;7(3):e31779. Epub 2012 Mar 9. PubMed PMID: 22427807; PubMed Central PMCID: PMC3302884.

The authors used RNAi knockdown and over-expression of Gyk and Dgk in the study, controlling expression of the RNAi reagent and ORFs with the Gal4-UAS system.

The authors indicate that mutations in the eye color genes brown, garnet, rosy, and vermillion, and the body color gene yellow modified glycerol hypersensitivity in the disease model flies.

Glycerol kinase deficiency is described at Wikipedia.
The relevant human genes at NCBI Gene include GK.
GK and the deficiency are described at OMIM.
Orphanet has some info on various forms of the deficiency.
Relevant fly genes include dGyk (Gyk in FlyBase) and dGK (Dgk in FlyBase).

Based on a DIOPT search, at least two other genes have significant similarity to GK, CG8298 and CG7995.

This review looks to be fairly comprehensive and includes comparison of DGKs in model species:  Mérida I, Avila-Flores A, Merino E. Diacylglycerol kinases: at the hub of cell signalling. Biochem J. 2008 Jan 1;409(1):1-18. Review. PubMed PMID: 18062770

Fly Models & Mental Retardation. Foundational Review.

This review is a little out-of-date due to the rapid pace of research. But it seems well worth the read. See for example Fig. 4, which summarizes the underlying biology, cell types, etc., and Table 3 and the Appendix tables, which summarize what was known then about a long list of putative fly orthologs of human genes linked to mental retardation.

Inlow JK, Restifo LL. Molecular and comparative genetics of mental retardation. Genetics. 2004 Feb;166(2):835-81. PubMed PMID: 15020472; PubMed Central PMCID: PMC1470723.

An advantage of a paper with a little age on it--free access through PubMed Central!

Tuesday, August 14, 2012

Methylene Blue and Huntington's Disease. Recent Report.

This recent report puts a fly model of Huntington's Disease to use in a study exploring the potential of methylene blue as a treatment for the disease.

Sontag EM, Lotz GP, Agrawal N, Tran A, Aron R, Yang G, Necula M, Lau A, Finkbeiner S, Glabe C, Marsh JL, Muchowski PJ, Thompson LM. Methylene Blue Modulates Huntingtin Aggregation Intermediates and Is Protective in Huntington's Disease Models. J Neurosci. 2012 Aug 8;32(32):11109-11119. PubMed PMID: 22875942.

The fly model used in the study is available from the BDSC. Stock number 6923.
Additional Huntington's Disease-related stocks at BDSC can be found here.

Alzheimer's Research in Worms and Flies. Recent Review.

Mhatre SD, Paddock BE, Saunders AJ, Marenda DR. Invertebrate Models of Alzheimer's Disease. J Alzheimers Dis. 2012 Aug 9. PubMed PMID: 22886023.

Related resource:  Alzheimer's Disease-related fly stocks at BDSC.

Thursday, August 9, 2012

Drosophila, chemical genetics and cancer. Recent Report.

Dar AC, Das TK, Shokat KM, Cagan RL. Chemical genetic discovery of targets and anti-targets for cancer polypharmacology. Nature. 2012 Jun 6;486(7401):80-4. doi: 10.1038/nature11127. PubMed PMID: 22678283.

From the abstract:
Combining kinase-focused chemistry, kinome-wide profiling and Drosophila genetics provides a powerful systems approach towards developing compounds with maximal therapeutic index.

Tuesday, August 7, 2012

Fly models of dilated cardiomyopathies. Recent review.

Wolf MJ. Modeling Dilated Cardiomyopathies in Drosophila. Trends Cardiovasc Med. 2012 Aug 2. PubMed PMID: 22863366.

The review includes a nice figure of the fly cardiovascular system (Fig. 2) and this statement in the Conclusions section:
Although the adult fly heart is a single cell layer thick and does not possess noncardiac cells found in mammalian hearts, the Drosophila model provides a system to examine the direct effects of gene mutations on size, morphology, and function of cardiomyocytes ... Ongoing investigations of the fly as a model for human cardiomyopathies have the potential to uncover new, fundamental mechanisms that are responsible for human cardiovascular diseases.

Fly research links innate immunity and neurodegenerative disease. Recent Review.

Petersen AJ, Wassarman DA. Drosophila innate immune response pathways moonlight in neurodegeneration. Fly (Austin). 2012 Jul 1;6(3). PubMed PMID: 22864563.

Relevant genes include tefu (also called ATM for Ataxia-telangiectasia mutated) and specifically, flies carrying the temperature-sensitive "8" allele of ATM are used as a model of Ataxia-telangiectasia (also called Louis-Bar syndrome). The relevant stock at the BDSC appears to be this one.

The review features work from these three research publications.

Petersen AJ, Rimkus SA, Wassarman DA. ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration in Drosophila. Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):E656-64. Epub 2012 Feb 21. PubMed PMID: 22355133; PubMed Central PMCID: PMC3306708.

Chinchore Y, Gerber GF, Dolph PJ. Alternative pathway of cell death in Drosophila mediated by NF-κB transcription factor Relish. Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):E605-12. Epub 2012 Feb 10. PubMed PMID: 22328149; PubMed Central PMCID: PMC3309745.

Tan L, Schedl P, Song HJ, Garza D, Konsolaki M. The Toll-->NFkappaB signaling pathway mediates the neuropathological effects of the human Alzheimer's Abeta42 polypeptide in Drosophila. PLoS One. 2008;3(12):e3966. Epub 2008 Dec 17. PubMed PMID: 19088848; PubMed Central PMCID: PMC2597734.

Heat-shock proteins and heart disease. Recent Review.

Hoogstra-Berends F, Meijering RA, Zhang D, Heeres A, Loen L, Seerden JP, Kuipers I, Kampinga HH, Henning RH, Brundel BJ. Heat Shock Protein-Inducing Compounds as Therapeutics to Restore Proteostasis in Atrial Fibrillation. Trends Cardiovasc Med. 2012 Aug 2. PubMed PMID: 22863365.

Atrial Fibrillation is a type of tachyarrhythmia of the heart.

This paper describing a Drosophila model of tachycardia is cited in the Hoogstra-Berends et al. review:  Zhang D, Ke L, Mackovicova K, Van Der Want JJ, Sibon OC, Tanguay RM, Morrow G, Henning RH, Kampinga HH, Brundel BJ. Effects of different small HSPB members on contractile dysfunction and structural changes in a Drosophila melanogaster model for Atrial Fibrillation. J Mol Cell Cardiol. 2011 Sep;51(3):381-9. PubMed PMID: 21745477

Watch the fly heart beat here:

Monday, August 6, 2012

KANSL1/wah in fly learning and microdeletion syndrome. Breaking Report.

Koolen DA, Kramer JM, Neveling K, Nillesen WM, Moore-Barton HL, Elmslie FV, Toutain A, Amiel J, Malan V, Tsai AC, Cheung SW, Gilissen C, Verwiel ET, Martens S, Feuth T, Bongers EM, de Vries P, Scheffer H, Vissers LE, de Brouwer AP, Brunner HG, Veltman JA, Schenck A, Yntema HG, de Vries BB. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat Genet. 2012 Apr 29;44(6):639-41. doi: 10.1038/ng.2262. PubMed PMID: 22544363

Relevant fly gene: waharan (wah) (also called NSL1)

The authors report that RNAi knockdown of wah in mushroom bodies in the fly brain can result in learning defects, providing supporting evidence for a functional link between the conserved KANSL1 gene and brain functions.

At OMIM the syndrome is referred to as autosomal dominant mental retardation-17 (MRD17).

At the cellular level, wah appears to be required for endosomal trafficking.  Read more here:  Lone M, Kungl T, Koper A, Bottenberg W, Kammerer R, Klein M, Sweeney ST, Auburn RP, O'Kane CJ, Prokop A. The nuclear protein Waharan is required for endosomal-lysosomal trafficking in Drosophila. J Cell Sci. 2010 Jul 15;123(Pt 14):2369-74. Epub 2010 Jun 15. PubMed PMID: 20551180; PubMed Central PMCID: PMC2894654.

Thursday, August 2, 2012

Spinocerebellar ataxia 1 stocks at the BDSC

Spinocerebellar ataxia type 1 (SCA1) is a progressive neurological disease caused by increases in the number of CAG repeats in the Ataxin 1 (ATXN1) gene. The Bloomington Drosophila Stock Center has recently acquired strains carrying human ATXN1 with differing numbers of CAG repeats for modeling SCA1 in flies (generated in Fernandez-Funez et al., 2000. Nature 408:101 pmid:11081516).

See these and other fly strains useful for studying SCA1 at the BDSC's SCA1 page.

Clocks & Neurodisease. Breaking Report.

This study looks at the effect of genetically disrupting circadian rhythms on neurodegeneration, and finds functional ties between the two.

Krishnan N, Rakshit K, Chow ES, Wentzell JS, Kretzschmar D, Giebultowicz JM. Loss of circadian clock accelerates aging in neurodegeneration-prone mutants. Neurobiol Dis. 2012 Mar;45(3):1129-35. PubMed PMID: 22227001; PubMed Central PMCID: PMC3291167.

Mutations in swi and sws are used in the study to model neurodegeneration.

The swi gene appears not to have been well conserved (no strong-scoring matches at DIOPT for example). By contrast, the sws gene has been conserved. The fly sws gene is related to the human gene PNPLA6 (also called NTE; Entrez Gene ID 10908). PNPLA6 is associated with spastic paraplegia 39, one of a group of spastic paraplegias. According to the literature summary at Entrez Gene, the normal role of the PNPLA6 protein is as a phopholipase that deacetyates intracellular phophatidylcholine, producing glycerophophocholine.

Mutations in per are used in the study to disrupt circadian rhythms.

The fly per gene has at least 3 putative orthologs in the human genome, PER1, PER2 and PER3. According to OMIM, mutations in PER2 are associated with familial advanced sleep phase syndrome.

Wednesday, August 1, 2012

Mitochondrial-related disease stocks at the BDSC

There are a variety of disorders caused by deficiencies in mitochondrial complex function. The Bloomington Drosophila Stock Center has recently posted a new page listing mitochondrial complex genes associated with human mitochondrial-related diseases along with fly stocks available at the BDSC for studying these genes and their function.

Go to the BDSC's Mitochondrial Disease Page.

Related Resources: See an overview of mitochondrial-related disorders at NIH's GeneReviews and a list of diseases at the United Mitochondrial Disease Foundation