Friday, September 28, 2012

SMBA & Poly-Q study. Recent report.

Jochum T, Ritz ME, Schuster C, Funderburk SF, Jehle K, Schmitz K, Brinkmann F, Hirtz M, Moss D, Cato AC. Toxic and non-toxic aggregates from the SBMA and normal forms of androgen receptor have distinct oligomeric structures. Biochim Biophys Acta. 2012 Jun;1822(6):1070-8. PubMed PMID: 22366762.

The authors indicate that they used two existing fly stocks, pUAST-ARQ22 and pUAST-ARQ22dm, and generated two new transgenic stocks, pUAST-ARQ1 and -ARQ65, for the study. These are pathogenic forms of the human androgen receptor protein. See this FlyBase page for more info on human AR transgenic flies. To induce expression of the AR forms, these authors used the OK371-GAL4 driver fly stock.

Circadian rhythms & fragile X. Fly models in action. Recent report.

This open access paper uses what is described as a Drosophila dfmr1 null mutant strain, dFmr1-Del3-21/TM6C, Kr:GFP.

Xu S, Poidevin M, Han E, Bi J, Jin P. Circadian rhythm-dependent alterations of gene expression in Drosophila brain lacking fragile X mental retardation protein. PLoS One. 2012;7(5):e37937. PubMed PMID: 22655085; PubMed Central PMCID: PMC3360013.

See also BDSC's fly stocks page for Fragile X Syndrome.
And a past post on a paper linking the circadian clock to neurodegenerative disease.

Tuesday, September 25, 2012

New fly model of Inclusion Body Myopathy 3. Recent report.

This study describes a new fly model based on introduction of a human disease-associated missense mutation (E706K) in myosin heavy chain IIa. The mutant form was introduced via P-element transformation and crossed into an Mhc null mutant background.

Wang Y, Melkani GC, Suggs JA, Melkani A, Kronert WA, Cammarato A, Bernstein SI. Expression of the inclusion body myopathy 3 mutation in Drosophila depresses myosin function and stability and recapitulates muscle inclusions and weakness. Mol Biol Cell. 2012 Jun;23(11):2057-65. Epub 2012 Apr 11. PubMed PMID: 22496423; PubMed Central PMCID: PMC3364171.

LRRK2 as a critical regulator of EndophilinA. Parkinson's model in action. Recent report.

From the abstract: "LRRK2-mediated EndoA phosphorylation has profound effects on EndoA-dependent membrane tubulation and membrane association ... and on synaptic vesicle endocytosis at Drosophila neuromuscular junctions in vivo." The authors report use of both loss-of-function and gain-of-function genetic approaches in the study.

Matta S, Van Kolen K, da Cunha R, van den Bogaart G, Mandemakers W, Miskiewicz K, De Bock PJ, Morais VA, Vilain S, Haddad D, Delbroek L, Swerts J, Chávez-Gutiérrez L, Esposito G, Daneels G, Karran E, Holt M, Gevaert K, Moechars DW, De Strooper B, Verstreken P. LRRK2 Controls an EndoA Phosphorylation Cycle in Synaptic Endocytosis. Neuron. 2012 Sep 20;75(6):1008-21. doi: 10.1016/j.neuron.2012.08.022. PubMed PMID: 22998870.

Click to see a post on a loss-of-function fly study of Lrrk2.
Or other posts on Parkinson's Disease.
Or other posts on neurodegeneration diseases of many types.

Monday, September 24, 2012

A-beta inhibitor tested in a fly model of Alzheimer's disease. Recent report.

McKoy AF, Chen J, Schupbach T, Hecht MH. A novel inhibitor of Aβ peptide aggregation: from high throughput screening to efficacy in an animal model for Alzheimer's disease. J Biol Chem. 2012 Sep 19. PubMed PMID: 22992731.

The fly model is described in the methods section as follows "female flies carrying the Aβ42 or Aβ42/E22G transgene under the UAS promoter in a homozygous condition ... crossed with male flies carrying the driver Elav[c155]-Gal4 on their X- chromosome."

Fly model of kidney stones. Recent report.

Hirata T, Cabrero P, Berholtz DS, Bondeson DP, Ritman EL, Thompson JR, Dow JA, Romero MF. In vivo Drosophila genetic model for calcium oxalate nephrolithiasis. Am J Physiol Renal Physiol. 2012 Sep 19. PubMed PMID: 22993075.

Relevant fly gene: Prestin (or dPrestin).
Nephrolithiasis is commonly known as kidney stones.

cAMP & Fragile X syndrome. Recent report.

Kanellopoulos AK, Semelidou O, Kotini AG, Anezaki M, Skoulakis EM. Learning and memory deficits consequent to reduction of the fragile x mental retardation protein result from metabotropic glutamate receptor-mediated inhibition of cAMP signaling in Drosophila. J Neurosci. 2012 Sep 19;32(38):13111-24. PubMed PMID: 22993428.

Chemical screen in fly tumor model. Recent report.

Free access available to this paper on chemical screening in a fly tumor model.

Willoughby LF, Schlosser T, Manning SA, Parisot JP, Street IP, Richardson HE, Humbert PO, Brumby AM. An in vivo large-scale chemical screening platform using Drosophila for anti-cancer drug discovery. Dis Model Mech. 2012 Sep 20. PubMed PMID: 22996645.

Friday, September 21, 2012

Fly wing genetic study helps define epigenetic network involved in cognition. Recent report.

This paper provides a nice example of how genetic studies in the fly can inform the interpretation of human disease-related next generation sequencing (NGS) results. 

Their Supplemental Table 7 lists the fly stocks they used in the study.

Kleefstra T, Kramer JM, Neveling K, Willemsen MH, Koemans TS, Vissers LE, Wissink-Lindhout W, Fenckova M, van den Akker WM, Kasri NN, Nillesen WM, Prescott T, Clark RD, Devriendt K, van Reeuwijk J, de Brouwer AP, Gilissen C, Zhou H, Brunner HG, Veltman JA, Schenck A, van Bokhoven H. Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. Am J Hum Genet. 2012 Jul 13;91(1):73-82. PubMed PMID: 22726846; PubMed Central PMCID: PMC3397275.

From the paper:

"Drosophila genetic interaction studies with established disease genes thus provide an efficient and, in our opinion, urgently required method of discriminating between rare or even unique benign DNA variants and causative mutations in the NGS era."

Crawling assay useful for assessing neurological disorder fly models. Recent report.

It's not just about your model fly. It's also about how you test it. 

This report describes a quantitative larval crawling assay that reveals impaired crawling in disease models of Alzheimer's disease (AD) and Fragile X syndrome. They also note that their findings with shaggy mutant animals might be relevant to the use of GSK-3 inhibitors in treating AD.

Jakubowski B, Longoria R, Shubeita G. A high throughput and sensitive method correlates neuronal disorder genotypes to Drosophila larvae crawling phenotypes. Fly (Austin). 2012 Sep 19;6(4). PubMed PMID: 22992470.

Thursday, September 20, 2012

Plant extract effects on rotenone-induced neurotoxicity. Recent report.

This report describes using Drosophila to test of the potential antioxidant properties of a plant extract.

Girish C, Muralidhara. Propensity of Selaginella delicatula aqueous extract to offset rotenone-induced oxidative dysfunctions and neurotoxicity in Drosophila melanogaster: Implications for Parkinson's disease. Neurotoxicology. 2012 Jun;33(3):444-56. PubMed PMID: 22521218.

As of this posting, the number of PubMed cataloged papers on Selaginella delicatula is small. It's a pteridophyte. Some previous posts point to papers looking at the effects of fruit extracts, methylene blue and L-ascorbic acid on fly neurodegeneration models.

Parkinson's associated LRRK2 ortholog study. Recent report.

This study describes analysis of loss-of-function of the Drosophila ortholog of LRRK2 (dLRRK), as well as analysis of the effects of over-expression of wild-type Drosophila and human LRRK2, and a pathogenic mutant form (hLRRK2-G2019S). The authors point out that LRRK2 is associated with familial and sporadic forms of Parkinson's Disease.

Lee S, Imai Y, Gehrke S, Liu S, Lu B. The synaptic function of LRRK2. Biochem Soc Trans. 2012 Oct 1;40(5):1047-51. PubMed PMID: 22988863.

Wednesday, September 19, 2012

Fly study links Ellis-van Creveld syndrome genes to Hedgehog pathway. Recent report.

Yang C, Chen W, Chen Y, Jiang J. Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2. Cell Res. 2012 Sep 18. doi: 10.1038/cr.2012.134. PubMed PMID: 22986504.

Additional ciliopathies for which there are putative fly orthologs of the human disease-associated genes include Ciliary Dykinesia, Joubert Syndrome and Bardet-Biedl Syndrome.

Drosophila as a model for lead toxicity. Recent report.

Hirsch HV, Lnenicka G, Possidente D, Possidente B, Garfinkel MD, Wang L, Lu X, Ruden DM. Drosophila melanogaster as a model for lead neurotoxicology and toxicogenomics research. Front Genet. 2012;3:68. PubMed PMID: 22586431; PubMed Central PMCID: PMC3343274.

The authors point out that parallels between the effects of lead poisoning and disorders such as attention deficit hyperactivity disorder (ADHD) suggest that studying lead neurotoxicology might have impact in additional fields of study.

Cohesinopathies. Recent review.

This review discusses fly and other models of cohesinopathies, which include Cornelia de Lange Syndrome and Roberts Syndrome.

Horsfield JA, Print CG, Mönnich M. Diverse developmental disorders from the one ring: distinct molecular pathways underlie the cohesinopathies. Front Genet. 2012;3:171. PubMed PMID: 22988450.

Among the genes discussed is Nipped-B, the fly ortholog of the human gene associated with Cornelia de Lange Syndrome. Table 1 of the review lists additional genes relevant to cohesinopathies.

Tuesday, September 18, 2012

Menkes and Wilsons Diseases. Recent report.

Menkes and Wilson diseases are related to copper homeostasis. This study looks at the Drosophila ortholog of the human genes associated with Menkes and Wilson diseases, Drosophila ATP7.

Sellami A, Wegener C, Veenstra JA. Functional significance of the copper transporter ATP7 in peptidergic neurons and endocrine cells in Drosophila melanogaster. FEBS Lett. 2012 Aug 16. PubMed PMID: 22981378.

Monday, September 17, 2012

Fly and mouse models of Alzheimer's Disease. Therapeutics development. Recent report.

Scherzer-Attali R, Farfara D, Cooper I, Levin A, Ben-Romano T, Trudler D, Vientrov M, Shaltiel-Karyo R, Shalev DE, Segev-Amzaleg N, Gazit E, Segal D, Frenkel D. Naphthoquinone-tyrptophan reduces neurotoxic Aβ*56 levels and improves cognition in Alzheimer's disease animal model. Neurobiol Dis. 2012 Jun;46(3):663-72. PubMed PMID: 22449754.

The fly model is described in the paper this way:  "Male flies carrying the driver elav-c155-Gal4 (on their X chromosome) were crossed to females carrying the Aβ1–42 transgene (located on an  autosome) under the UAS promoter in a homozygous condition. This resulted in first generation (F1) female offspring expressing Aβ1–42 in their nervous system. ... Male F1 offspring, which carried the Aβ1–42 transgene but did not express it (because they lacked the Gal4 driver) served as a control."

Resources related Alzheimer's Disease:

Alzheimer Research Forum
BDSC's AD fly stocks page
Past posts on AD

Fly models of neurodegenerative disease. Recent review.

This recent review has an emphasis on forward genetic screens, such as screens for the 'bang sensitive' phenotype or for short-lived flies, or using electroretinograms.

Jaiswal M, Sandoval H, Zhang K, Bayat V, Bellen HJ. Probing Mechanisms that Underlie Human Neurodegenerative Disease in Drosophila. Annu Rev Genet. 2012 Sep 4. PubMed PMID: 22974305.

Thursday, September 13, 2012

Fly mauve mutant as model for Chediak-Higashi syndrome. Recent report.

This report describes a new fly model of Chediak-Higashi syndrome (CHS), a disease affecting lysosomes.

Rahman M, Haberman A, Tracy C, Ray S, Kramer H. Drosophila mauve mutants reveal a role of LYST homologs late in the maturation of phagosomes and autophagosomes. Traffic. 2012 Aug 30. doi: 10.1111/tra.12005. PubMed PMID: 22934826.

As of this posting, FlyBase has separate records for mauve (FBgn0014363) and the sequenced region identified as mauve in the paper, CG42863 (FBgn0262110). The CG number or its FlyBase ID pulls up results with a FlyMine search (mauve does not yet match to FlyMine records).

Genes related to fly eye color have contributed to the study of other disease models. See for example this post on a fly glycerol kinase deficiency model.

Looking to get started learning more about CHS? There is summary information about the disease available at GeneReviews.

Drosophila neurodegeneration model and proteomics. Conserved findings. Recent report.

Wishart TM, Rooney TM, Lamont DJ, Wright AK, Morton AJ, Jackson M, Freeman MR, Gillingwater TH. Combining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo. PLoS Genet. 2012 Aug;8(8):e1002936. PubMed PMID: 22952455; PubMed Central PMCID: PMC3431337

From the abstract:  "... An initial screen targeting thirteen degeneration-associated proteins using mutant Drosophila lines revealed six potential regulators of synaptic and axonal degeneration in vivo. Mutations in CALB2, ROCK2, DNAJC5/CSP, and HIBCH partially delayed injury- nduced neurodegeneration. Conversely, mutations in DNAJC6 and ALDHA1 led to spontaneous degeneration of distal axons and synapses. A more detailed genetic analysis ..."

Wednesday, September 12, 2012

Disease-related ortholog tool improved. DIOPT-DIST with fuzzy search.

The DRSC has just updated the DIOPT-DIST tool to allow for more 'forgiving' searches in the search field, "Or disease full text search."

Before, a search with "Parkinson" might pull up different results than a search with "Parkinson's" or "Parkinsonism" would deliver. Now, all these terms pull up the same list, and even a misspelling like "Parksinson" will get you where you mean to be.

The back end does not have an extensive set of disease synonyms, so the DRSC still suggests trying different synonyms of diseases (or OMIM IDs). But hopefully the fuzzy search will make things a whole lot easier.

Flies on a death spiral. Modeling physiological decline. Recent report.

This recent study describes several assays that can be used to assess physiological and age-related decline in flies.

Shahrestani P, Tran X, Mueller LD. Physiology declines prior to death in Drosophila melanogaster. Biogerontology. 2012 Sep 9. [Epub ahead of print] PubMed PMID: 22960750.

Monday, September 10, 2012

Charcot Marie Tooth Syndrome and Atypical Optic Atrophy. Recent report.

Eschenbacher WH, Song M, Chen Y, Bhandari P, Zhao P, Jowdy CC, Engelhard JT, Dorn GW 2nd. Two rare human mitofusin 2 mutations alter mitochondrial dynamics and induce retinal and cardiac pathology in Drosophila. PLoS One. 2012;7(9):e44296. PubMed PMID: 22957060

See also all posts on CMT.

Fragile-X. Recent report.

Another paper describing use of a fly model of a neurodegenerative disease.

Qurashi A, Liu H, Ray L, Nelson DL, Duan R, Jin P. Chemical screen reveals small molecules suppressing fragile X premutation rCGG repeat-mediated neurodegeneration in Drosophila. Hum Mol Genet. 2012 May 1;21(9):2068-75. PubMed PMID: 22298836; PubMed Central PMCID: PMC3315210.

Related resource:  BDSC's page on fly stocks related to fragile-X syndrome.

AD fly model and mitochondria. Recent report.

Open access paper using a fly model of Alzhemer's Disease.

Iijima-Ando K, Sekiya M, Maruko-Otake A, Ohtake Y, Suzuki E, Lu B, Iijima KM. Loss of Axonal Mitochondria Promotes Tau-Mediated Neurodegeneration and Alzheimer's Disease-Related Tau Phosphorylation Via PAR-1. PLoS Genet. 2012 Aug;8(8):e1002918. PubMed PMID: 22952452.

Friday, September 7, 2012

Progressive External Ophthalmoplegia. Recent report.

This open access paper reports a new in vivo fly model of disease, in this case modeling autosomal dominant progressive external ophthalmoplegia (adPEO).

Sanchez-Martinez A, Calleja M, Peralta S, Matsushima Y, Hernandez-Sierra R, Whitworth AJ, Kaguni LS, Garesse R. Modeling pathogenic mutations of human twinkle in Drosophila suggests an apoptosis role in response to mitochondrial defects. PLoS One. 2012;7(8):e43954. PubMed PMID: 22952820

The fly gene used to model the disease in flies is referred to in the paper as d-mtDNA helicase (d-mtDNA). It has the systematic name CG5924 and the FlyBase ID FBgn0032154.

FlyBase lists 2 TRiP RNAi fly stocks and two additional stocks for CG5924 available from the BDSC, as well as one RNAi fly stock at the VDRC and one transposon insertion strain in the Exilixis collection at HMS. These resources would be useful to study the reduction-of-function phenotypes of the gene, which in this case is different from the disease model, which is based on over-expression.

A related reduction-of-function (RNAi) and over-expression study in fly cells is described in this paper: Matsushima Y, Kaguni LS. Differential phenotypes of active site and human autosomal dominant progressive external ophthalmoplegia mutations in Drosophila mitochondrial DNA helicase expressed in Schneider cells. J Biol Chem. 2007 Mar 30;282(13):9436-44. PubMed PMID: 17272269.

To read more about adPEO and related diseases or disorders, consider starting here:

adPEO attributed to the twinkle gene at OMIM
PEO search results at OMIM (additional related diseases)
POLG-related disorders at Gene Reviews
Mitochondrial diseases overview at Gene Reviews
Related research projects listed at Orphanet
Info on PEO at Genetics Home Reference

Recommended search term for finding more putative orthologs of PEO-related human disease genes at DIOPT-DIST is "ophthalmoplegia" (without quote marks) in the box "Or disease full text search."

Thursday, September 6, 2012

Fruit extracts and neurodegeneration. Recent report.

This recent report describes testing the potential therapeutic effects of fruit-derived compounds using a fly model of neurodegenerative disease (a transgenic fly strain expressing human A-beta-42).

Yu Y, Feng XL, Gao H, Xie ZL, Dai Y, Huang XJ, Kurihara H, Ye WC, Zhong Y, Yao XS. Chemical constituents from the fruits of Gardenia jasminoides Ellis. Fitoterapia. 2012 Apr;83(3):563-7. PubMed PMID: 22245087

Models like this in which a disease-associated human gene is expressed in flies are available from the BDSC. Check out BDSC's page on Alzheimers disease fly stocks for example.

Immunity and age-related disease. Recent review.

This open access review discusses fly models related to aging and immunity.

Eleftherianos I, Castillo JC. Molecular mechanisms of aging and immune system regulation in Drosophila. Int J Mol Sci. 2012;13(8):9826-44. PubMed PMID: 22949833

Using Drosophila to study obesity and diabetes. Recent mini-review.

This recent mini-review provides an overview and references for specific models.

Teleman AA, Ratzenböck I, Oldham S. Drosophila: a model for understanding obesity and diabetic complications. Exp Clin Endocrinol Diabetes. 2012 Apr;120(4):184-5. PubMed PMID: 22402943.

Wednesday, September 5, 2012

Parkinson's Disease, Miro and Mitochondria. Recent Report.

Liu S, Sawada T, Lee S, Yu W, Silverio G, Alapatt P, Millan I, Shen A, Saxton W, Kanao T, Takahashi R, Hattori N, Imai Y, Lu B. Parkinson's disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria. PLoS Genet. 2012;8(3):e1002537. PubMed PMID: 22396657; PubMed Central PMCID: PMC3291531.

Related resource: BDSC's collection of Parkinson's disease-related fly stocks.
RNAi fly stocks for dMiro are available from the VDRC and TRiP--see FlyBase record for dMiro.

Tuesday, September 4, 2012

Comparison of the glycobiology of humans and flies. Foundational review.

In this recent review, the authors provide a comparison of human and fly glycobiology and describe the "increasing opportunities to dissect pathologic mechanisms using Drosophila genetics."

Katoh T, Tiemeyer M. The N's and O's of Drosophila glycoprotein glycobiology. Glycoconj J. 2012 Aug 31. PubMed PMID: 22936173

The authors indicate that the proteins and pathways discussed are relevant to a number of diseases, including retinitis pigmentosa, Peters Plus syndrome, and diseases "such as autoimmunity, cancer progression, and congenital heart disease, in which altered mucin type O-glycosylation has been implicated." 

Peters Plus syndrome is also known as Krause–van Schooneveld–Kivlin syndrome and Krause–Kivlin syndrome. It is listed on Orphanet and you can read more about it at GeneReviews.

If someone has the time and inclination to pull out the Drosophila gene names mentioned in the paper, and list them as a comment here, please do so.