Friday, August 28, 2015

Characterization of fly model of classic galactosemia

Jumbo-Lucioni P, Parkinson W, Broadie K. Overelaborated synaptic architecture and reduced synaptomatrix glycosylation in a Drosophila classic galactosemia disease model. Dis Model Mech. 2014 Dec;7(12):1365-78. doi: 10.1242/dmm.017137. PMID: 25326312; PMCID: PMC4257005.

From the abstract: "Classic galactosemia (CG) is an autosomal recessive disorder resulting from loss of galactose-1-phosphate uridyltransferase (GALT), which catalyzes conversion of galactose-1-phosphate and uridine diphosphate (UDP)-glucose to glucose-1-phosphate and UDP-galactose, immediately upstream of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine synthesis. ... Here, we characterize behavioral traits, synaptic development and glycosylated synaptomatrix formation in a GALT-deficient Drosophila disease model. ... These results reveal synaptomatrix glycosylation losses, altered trans-synaptic signaling pathway components, defective synaptogenesis and impaired coordinated movement in a CG neurological disease model."

Review--fly as model for studying role of glia in neurodegeneration

Lee YM, Sun YH. Drosophila as a model to study the role of glia in neurodegeneration. J Neurogenet. 2015 Aug 27:1-11. PMID: 26312528.

From the abstract: "Neurons and glia interact reciprocally. ... Neurodegenerative diseases are usually late-onset, progressive, and affect specific parts of the nervous system. ... The events that occur in glia, and whether and how glia participate in the pathogenesis of these diseases, have not been as well studied. In this review, we will focus on how the fruit fly Drosophila melanogaster has been used as a model to study neuron-glia interactions in neurodegenerative disorders ..."

Friday, August 21, 2015

Review--flies and prion disease

Bujdoso R, Landgraf M, Jackson WS, Thackray AM. Prion-induced neurotoxicity: Possible role for cell cycle activity and DNA damage response. World J Virol. 2015 Aug 12;4(3):188-97. PMID:
26279981; PMCID: PMC4534811.

From the abstract: "Protein misfolding neurodegenerative diseases arise through neurotoxicity induced by aggregation of host proteins. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, motor neuron disease, tauopathies and prion diseases. ... Prion diseases are an important paradigm for neurodegenerative conditions in general ... Here we review the role of cell cycle activity and the DNA damage response in neurodegeneration associated with protein misfolding diseases ... In doing so, we highlight PrP transgenic Drosophila as a tractable model for the genetic analysis of transmissible mammalian prion disease."

Review--how fly research has and can continue to contribute to understanding intellectual disability

van der Voet M, Nijhof B, Oortveld MA, Schenck A. Drosophila models of early onset cognitive disorders and their clinical applications. Neurosci Biobehav Rev. 2014 Oct;46 Pt 2:326-42. PMID: 24661984.

From the abstract: "... For the extremely large, genetically and phenotypically heterogeneous group of intellectual disability (ID) disorders, more than 600 causative genes have been identified to date. However, knowledge about the molecular mechanisms and networks disrupted by these genetic aberrations is lagging behind. The fruit fly Drosophila has emerged as a powerful model organism to close this knowledge gap. This review summarizes recent achievements that have been made in this model and envisions its future contribution to our understanding of ID genetics and neuropathology. ... In conclusion, Drosophila provides many opportunities to advance future medical genomics of early onset cognitive disorders."

Review--Drosophila research contribution to understaning polyQ diseases

Xu Z, Tito A, Rui YN, Zhang S. Studying Polyglutamine Diseases in Drosophila. Exp Neurol. 2015 Aug 6. pii: S0014-4886(15)30063-7. PMID: 26257024.

From the abstract: "Polyglutamine (polyQ) diseases are a family of dominantly transmitted neurodegenerative disorders caused by an abnormal expansion of CAG trinucleotide repeats in the protein-coding regions of the respective disease-causing genes. ... Over the past two decades, Drosophila has proven to be successful in modeling this family of neurodegenerative disorders, including the faithful recapitulation of pathological features such as ... neuronal degeneration. Additionally, it has been valuable in probing the pathogenic mechanisms, in identifying and evaluating disease modifiers, and in helping elucidate the normal functions of disease-causing genes. Knowledge learned from this simple invertebrate organism has had a large impact on our understanding of these devastating brain diseases."

Study focused on gastric cancer includes assays in flies

Caldeira J, Figueiredo J, Brás-Pereira C, Carneiro P, Moreira AM, Pinto MT, Relvas JB, Carneiro F, Barbosa M, Casares F, Janody F, Seruca R. E-cadherin-defective gastric cancer cells depend on Laminin to survive and invade. Hum Mol Genet. 2015 Aug 5. pii: ddv312. PMID: 26246502.

From the abstract: "Epithelial-cadherin (Ecad) deregulation affects cell-cell adhesion and results in increased invasiveness of distinct human carcinomas. ... To verify whether matrix deregulation was triggered by Ecad loss, we used the Drosophila model. To dissect the key molecules involved and unveil their functional significance, we used gastric cancer cell lines. ..."

Fly provides genetic insights into Parkinson's associated mutations in VPS35 (PARK17)

Malik BR, Godena VK, Whitworth AJ. VPS35 pathogenic mutations confer no dominant toxicity but partial loss of function in Drosophila and genetically interact with parkin. Hum Mol Genet. 2015 Aug 6. pii: ddv322. PMID: 26251041.

From the abstract: "Mutations in VPS35 (PARK17) cause autosomal dominant, late onset Parkinson's disease (PD). ... we generated transgenic Drosophila that express variant forms of human VPS35 found in PD cases and the corresponding variants of the Drosophila ortholog. We did not find evidence of dominant toxicity ... we found that the D620N mutation confers a partial loss of function. Recently, VPS35 has been linked to the formation of mitochondria-derived vesicles, which mediate the degradation of mitochondrial proteins and contribute to mitochondrial quality control. This process is also promoted by two other PD-lined genes parkin (PARK2) and PINK1 (PARK6). We demonstrate here that vps35 genetically interacts with parkin but interestingly not with pink1. Strikingly, Vps35 overexpression is able to rescue several parkin-mutant phenotypes. Together these findings provide in vivo evidence that the D620N mutation likely confers pathogenicity through a partial loss of function mechanism and that this may be linked to other known pathogenic mechanisms such as mitochondrial dysfunction."

Studies in fly and mouse help elucidate causes and possible therapeutic for erythrokeratodermia variabilis

Tang C, Chen X, Chi J, Yang D, Liu S, Liu M, Pan Q, Fan J, Wang D, Zhang Z. Pathogenic Cx31 Is Un/misfolded to Cause Skin Abnormality via A Fos/JunB-Mediated Mechanism. Hum Mol Genet. 2015 Aug 6. PMID: 26251042.

From the abstract: "Mutations in connexin-31 (Cx31) are associated with multiple human diseases, including familial erythrokeratodermia variabilis (EKV). The pathogenic mechanism of EKV associated Cx31 mutants remains largely elusive. Here, we show that EKV pathogenic Cx31 mutants are un/misfolded and temperature sensitive. In Drosophila, expression of pathogenic Cx31, but not wildtype Cx31, causes depigmentation and degeneration of ommatidia that are rescued by expression of either dBip or dHsp70. Ectopic expression of Cx31 in mouse skin results in skin abnormalities resembling human EKV. The affected tissues show remarkable disrupted gap junction formation and significant upregulation of chaperones Bip and Hsp70 as well as AP-1 proteins c-Fos and JunB, in addition to molecular signatures of skin diseases. ..."

Thursday, August 20, 2015

Proteomics analysis used to explore conserved networks relavant to Parkinson's Disease

Zhang S, Xie J, Xia Y, Yu S, Gu Z, Feng R, Luo G, Wang D, Wang K, Jiang M, Cheng X, Huang H, Zhang W, Wen T. LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration. Sci Rep. 2015 Jul 29;5:12564. doi: 10.1038/srep12564. PMID: 26220523

From the abstract: "Parkinson's disease (PD) is a movement disorder due to the loss of dopaminergic (DA) neurons in the substantia nigra. Alpha-synuclein phosphorylation and α-synuclein inclusion (Lewy body) become a main contributor, but little is known about their formation mechanism. Here we used protein expression profiling of PD to construct a model of their signalling network from drsophila to human and nominate major nodes that regulate PD development. ..."

Fly models of Parkinson's disease used in two studies focused on LRKK2

Schreij AM, Chaineau M, Ruan W, Lin S, Barker PA, Fon EA, McPherson PS. LRRK2 localizes to endosomes and interacts with clathrin-light chains to limit Rac1 activation. EMBO Rep. 2015 Jan;16(1):79-86. PMID: 25427558; PMCID: PMC4304731.

From the abstract: "Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of dominant-inherited Parkinson's disease (PD), and yet we do not fully understand the physiological function(s) of LRRK2. Various components of the clathrin machinery have been recently found mutated in familial forms of PD. Here, we provide molecular insight into the association of LRRK2 with the clathrin machinery. We report that through its GTPase domain, LRRK2 binds directly to clathrin-light chains (CLCs). ... In Drosphila, a minimal rough eye phenotype caused by overexpression of Rac1, is dramatically enhanced by loss of function of CLC and LRRK2 homologues, confirming the importance of this pathway in vivo. Our data identify a new pathway in which CLCs function with LRRK2 to control Rac1 activation on endosomes, providing a new link between the clathrin machinery, the cytoskeleton and PD."

Lin CH, Li H, Lee YN, Cheng YJ, Wu RM, Chien CT. Lrrk regulates the dynamic profile of dendritic Golgi outposts through the golgin Lava lamp. J Cell Biol. 2015 Aug 3;210(3):471-83. PMID: 26216903; PMCID: PMC4523617.

From the abstract: "Constructing the dendritic arbor of neurons requires dynamic movements of Golgi outposts (GOPs), the prominent component in the dendritic secretory pathway. ... Here, we show that Leucine-rich repeat kinase (Lrrk), the Drosophila melanogaster homologue of Parkinson's disease-associated Lrrk2, regulates GOP dynamics in dendrites. ... Whereas overexpression of kinase-dead Lrrk caused dominant-negative effects on GOP dynamics, overexpression of the human LRRK2 mutant G2019S with augmented kinase activity promoted retrograde movement. Our study reveals a pathogenic pathway for LRRK2 mutations causing dendrite degeneration."

Genetic screen in Drosophila identifies molecular link betwen JNK signaling and polarity -- cancer relevance

Andersen DS, Colombani J, Palmerini V, Chakrabandhu K, Boone E, Röthlisberger M, Toggweiler J, Basler K, Mapelli M, Hueber AO, Léopold P. The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth. Nature. 2015 Jun 25;522(7557):482-6. PMID: 25874673.

From the abstract: "Disruption of epithelial polarity is a key event in the acquisition of neoplastic growth. JNK signalling is known to play an important part in driving the malignant progression of many epithelial tumours, although the link between loss of polarity and JNK signalling remains elusive. In a Drosophila genome-wide genetic screen designed to identify molecules implicated in neoplastic growth, we identified grindelwald (grnd) ... Grnd represents the first example of a TNFR that integrates signals from both Egr and apical polarity determinants to induce JNK-dependent cell death or tumour growth. "

Parkinson's disease model flies included in study related to mitochondrial function

Senyilmaz D, Virtue S, Xu X, Tan CY, Griffin JL, Miller AK, Vidal-Puig A, Teleman AA. Regulation of mitochondrial morphology and function by stearoylation of TFR1. Nature. 2015 Jul 27. PMID: 26214738.

From the abstract:
"Mitochondria are involved in a variety of cellular functions, ... Mitochondrial dysfunction has been linked to neurodegenerative diseases, cancer and ageing. ... Here we identify the metabolite stearic acid (C18:0) and human transferrin receptor 1 (TFR1; also known as TFRC) as mitochondrial regulators. ... Intriguingly, dietary C18:0 supplementation can counteract the mitochondrial dysfunction caused by genetic defects such as loss of the Parkinson's disease genes Pink or Parkin in Drosophila. This work identifies the metabolite C18:0 as a signalling molecule regulating mitochondrial function in response to diet."

Run, sleep and thrive

Zheng L, Feng Y, Wen DT, Wang H, Wu XS. Fatiguing exercise initiated later in life reduces incidence of fibrillation and improves sleep quality in Drosophila. Age (Dordr). 2015 Aug;37(4):9816. PMID: 26206392; PMCID: PMC4512962.

From the abstract: "As the human body ages, the risk of heart disease and stroke greatly increases. While there is evidence that lifelong exercise is beneficial to the heart's health, the effects of beginning exercise later in life remain unclear. This study aimed to investigate whether exercise training started later in life is beneficial to cardiac aging in Drosophila. ... We found that 2.0 and 2.5 h of exercise caused exercise-induced fatigue, and fatiguing exercise is beneficial for cardiac and healthy aging overall. This study provides a basis for further study in humans on the impact of beginning an exercise regimen later in life on cardiac health. "

Flies, podocytes and diabetic nephropathy

Na J, Sweetwyne MT, Park AS, Susztak K, Cagan RL. Diet-Induced Podocyte Dysfunction in Drosophila and Mammals. Cell Rep. 2015 Jul 28;12(4):636-47. PMID: 26190114; PMCID: PMC4532696.

From the abstract: "Diabetic nephropathy is a major cause of end-stage kidney disease. Characterized by progressive microvascular disease, most efforts have focused on injury to the glomerular endothelium. Recent work has suggested a role for the podocyte, a highly specialized component of the glomerular filtration barrier. Here, we demonstrate that the Drosophila nephrocyte, a cell analogous to the mammalian podocyte, displays defects that phenocopy aspects of diabetic nephropathy in animals fed chronic high dietary sucrose. Through functional studies, we identify an OGT-Polycomb-Knot-Sns pathway that links dietary sucrose to loss of the Nephrin ortholog Sns ..."

Wednesday, August 19, 2015

New fly model of ALS -- temporarl and spatial control of TDP-43 expression

Cheng CW, Lin MJ, Shen CJ. Rapamycin Alleviates Pathogenesis of a New Drosophila Model of ALS-TDP. J Neurogenet. 2015 Jul 29:1-47. PMID: 26219309.

From the abstract: "... We describe the generation and characterization of a new fly model of ALS-TDP with transgenic expression of the Drosophila ortholog of TDP-43, dTDP, in adult flies under the control of a temperature sensitive motor neuron-specific GAL4, thus bypassing the deleterious effect of dTDP during development. ... In sum, this Drosophila model of ALS-TDP under temporal and spatial control presents a useful new genetic tool for the screening and validation of therapeutic drugs for ALS. Furthermore, the data support our previous finding that autophagy activators including rapamycin are potential therapeutic drugs for the progression of neurodegenerative diseases with TDP-43 proteinopathies."

Wednesday, August 5, 2015

Review--fly models of Huntington's disease

From the abstract: "there has been a significant contribution to our understating of the disease from studies utilizing Drosophila melanogaster. Flies have a Htt protein, so the endogenous pathways with which it interacts are likely conserved. Transgenic flies engineered to overexpress the human mutant HTT gene display protein aggregation, neurodegeneration, behavioural deficits and a reduced lifespan. The short life span of flies, low cost of maintaining stocks and genetic tools available for in vivo manipulation make them ideal for the discovery of new genes that are involved in HD pathology."

Tuesday, August 4, 2015

Adult fly leg as "valuable new tool" for study of TDP-43-mediated degeneration of motor neurons

Sreedharan J, Neukomm LJ, Brown RH Jr, Freeman MR. Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2. Curr Biol. 2015 Jul 28. pii: S0960-9822(15)00739-3. PMID: 26234214.

From the abstract: "The RNA-processing protein TDP-43 is central to the pathogenesis of amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron (MN) disease [1-4]. TDP-43 is conserved in Drosophila ... We used a mosaic approach to study age-dependent MN loss in the adult fly leg where it is possible to resolve single motor axons, NMJs and active zones, and perform rapid forward genetic screens. We show that expression of TDP-43Q331K caused dying-back of NMJs and axons ... We report the identification of three genes that suppress TDP-43 toxicity ... In addition to delineating genetic factors that modify TDP-43 toxicity, these results establish the Drosophila adult leg as a valuable new tool for the in vivo study of adult MN phenotypes."

Methods review -- use of fly to model early stages of Alzheimer's disease

Lim JY, Ott S, Crowther DC. Drosophila melanogaster as a Model for Studies on the Early Stages of Alzheimer's Disease. Methods Mol Biol. 2016;1303:227-39. PMID: 26235070.

Review highlights usefulness of Drosophila as a model for study of congenital heart disease

Vogler G, Bodmer R. Cellular Mechanisms of Drosophila Heart Morphogenesis. J Cardiovasc Dev Dis. 2015 Mar 1;2(1):2-16.  PMID: 26236710

From the abstract: "Many of the major discoveries in the fields of genetics and developmental biology have been made using the fruit fly, Drosophila melanogaster. With regard to heart development, the conserved network of core cardiac transcription factors that underlies cardiogenesis has been studied in great detail in the fly, and the importance of several signaling pathways that regulate heart morphogenesis, such as Slit/Robo, was first shown in the fly model. ... The specific limitations of the various cardiac model systems currently employed (mammalian and fish models) provide a niche for the fly model ... Here, we review recent advances made using the Drosophila embryo that identify factors relevant for heart formation. ..."