[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content

Advertisement

Springer Nature Link
Log in

Acute and chronic metal exposure impairs locomotion activity in Drosophila melanogaster: a model to study Parkinsonism

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

The biometals iron (Fe), manganese (Mn) and copper (Cu) have been associated to Parkinson’s disease (PD) and Parkinsonism. In this work, we report for the first time that acute (15 mM for up to 5 days) or chronic (0.5 mM for up to 15 days) Fe, Mn and Cu exposure significantly reduced life span and locomotor activity (i.e. climbing capabilities) in Drosophila melanogaster. It is shown that the concentration of those biometals dramatically increase in Drosophila’s brain acutely or chronically fed with metal. We demonstrate that the metal accumulation in the fly’s head is associated with the neurodegeneration of several dopaminergic neuronal clusters. Interestingly, it is found that the PPL2ab DAergic neuronal cluster was erode by the three metals in acute and chronic metal exposure and the PPL3 DAergic cluster was also erode by the three metals but in acute metal exposure only. Furthermore, we found that the chelator desferoxamine, ethylenediaminetetraacetic acid, and d-penicillamine were able to protect but not rescue D. melanogaster against metal intoxication. Taken together these data suggest that iron, manganese and copper are capable to destroy DAergic neurons in the fly’s brain, thereby impairing their movement capabilities. This work provides for the first time metal-induced Parkinson-like symptoms in D. melanogaster. Understanding therefore the effects of biometals in the Drosophila model may provide insights into the toxic effect of metal ions and more effective therapeutic approaches to Parkinsonism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Atasoy HT, Nuyan O, Tunc T, Yorubulut M, Unal AE, Inan LE (2004) T2-weighted MRI in Parkinson’s disease; substantia nigra pars compacta hypointensity correlates with the clinical scores. Neurol India 52(3):332–337

    PubMed  Google Scholar 

  • Au C, Benedetto A, Aschner M (2008) Manganese transport in eukaryotes: the role of DMT1. Neurotoxicology 29(4):569–576

    Article  PubMed  CAS  Google Scholar 

  • Bahadorani S, Bahadorani P, Marcon E, Walker DW, Hilliker AJ (2010) A Drosophila model of Menkes disease reveals a role for DmATP7 in copper absorption and neurodevelopment. Dis Model Mech 3(1–2):84–891

    Article  PubMed  CAS  Google Scholar 

  • Ben-Shachar D, Youdim MBH (1991) Intranigral iron injection induces behavioral and biochemical “Parkinsonism” in rats. J Neurochem 57:2133–2135

    Article  PubMed  CAS  Google Scholar 

  • Berg D (2006) In vivo detection of iron and neuromelanin by transcranial sonography—a new approach for early detection of substantia nigra damage. J Neural Transm 113(6):775–780

    Article  PubMed  CAS  Google Scholar 

  • Brar S, Henderson D, Schenck J, Zimmerman EA (2009) Iron accumulation in the substantia nigra of patients with Alzheimer disease and Parkinsonism. Arch Neurol 66(3):371–374

    Article  PubMed  Google Scholar 

  • Burke R, Commons E, Camakaris J (2008) Expression and localisation of the essential copper transporter DmATP7 in Drosophila neuronal and intestinal tissues. Int J Biochem Cell Biol 40(9):1850–1860

    Article  PubMed  CAS  Google Scholar 

  • Burton NC, Guilarte TR (2009) Manganese neurotoxicity: lessons learned from longitudinal studies in nonhuman primates. Environ Health Perspect 117(3):325–332

    Article  PubMed  CAS  Google Scholar 

  • Cass WA, Grondin R, Andersen AH, Zhang Z, Hardy PA, Hussey-Andersen LK, Rayens WS, Gerhardt GA, Gash DM (2007) Iron accumulation in the striatum predicts aging-related decline in motor function in rhesus monkeys. Neurobiol Aging 28(2):258–271

    Article  PubMed  CAS  Google Scholar 

  • Chaudhuri A, Bowling K, Funderburk C, Lawal H, Inamdar A, Wang Z, O’Donnell JM (2007) Interaction of genetic and environmental factors in a Drosophila Parkinsonism model. J Neurosci 27(10):2457–2467

    Article  PubMed  CAS  Google Scholar 

  • Costello DJ, Walsh SL, Harrington HJ, Walsh CH (2004) Concurrent hereditary haemochromatosis and idiopathic Parkinson’s disease: a case report series. J Neurol Neurosurg Psychiatry 75(4):631–633

    Article  PubMed  CAS  Google Scholar 

  • Coulom H, Birman S (2004) Chronic exposure to rotenone models sporadic Parkinson’s disease in Drosophila melanogaster. J Neurosci 24(48):10993–10998

    Article  PubMed  CAS  Google Scholar 

  • Das SK, Ray K (2006) Wilson’s disease: an update. Nat Clin Pract Neurol 2(9):482–493

    Article  PubMed  Google Scholar 

  • Dexter DT, Jenner P, Schapira AH, Marsden CD (1992) Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. The Royal Kings and Queens Parkinson’s Disease Research Group. Ann Neurol 32(Suppl):S94–S100

    Article  PubMed  CAS  Google Scholar 

  • Discalzi G, Pira E, Herrero Hernandez E, Valentini C, Turbiglio M, Meliga F (2000) Occupational Mn Parkinsonism: magnetic resonance imaging and clinical patterns following CaNa2-EDTA chelation. Neurotoxicology 21(5):863–866

    PubMed  CAS  Google Scholar 

  • Dydak U, Jiang YM, Long LL, Zhu H, Chen J, Li WM, Edden RA, Hu S, Fu X, Long Z, Mo XA, Meier D, Harezlak J, Aschner M, Murdoch JB, Zheng W (2011) In vivo measurement of brain GABA concentrations by magnetic resonance spectroscopy in smelters occupationally exposed to manganese. Environ Health Perspect 119(2):219–224

    Article  PubMed  CAS  Google Scholar 

  • Egli D, Selvaraj A, Yepiskoposyan H, Zhang B, Hafen E, Georgiev O, Schaffner W (2003) Knockout of ‘metal-responsive transcription factor’ MTF-1 in Drosophila by homologous recombination reveals its central role in heavy metal homeostasis. EMBO J 22(1):100–108

    Article  PubMed  CAS  Google Scholar 

  • Forno LS (1996) Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 55:259–272

    Article  PubMed  CAS  Google Scholar 

  • Gallez B, Baudelet C, Adline J, Geurts M, Delzenne N (1997) Accumulation of manganese in the brain of mice after intravenous injection of manganese-based contrast agents. Chem Res Toxicol 10(4):360–363

    Article  PubMed  CAS  Google Scholar 

  • Graham JM, Paley MN, Grünewald RA, Hoggard N, Griffiths PD (2000) Brain iron deposition in Parkinson’s disease imaged using the PRIME magnetic resonance sequence. Brain 123(Pt 12):2423–2431

    Article  PubMed  Google Scholar 

  • Guilarte TR (2010) Manganese and Parkinson’s disease: a critical review and new findings. Environ Health Perspect 118(8):1071–1080

    Article  PubMed  CAS  Google Scholar 

  • Hua H, Georgiev O, Schaffner W, Steiger D (2010) Human copper transporter Ctr1 is functional in Drosophila, revealing a high degree of conservation between mammals and insects. J Biol Inorg Chem 15(1):107–113

    Article  PubMed  CAS  Google Scholar 

  • Huster D (2010) Wilson disease. Best Pract Res Clin Gastroenterol 24(5):531–539

    Article  PubMed  CAS  Google Scholar 

  • Jankovic J (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79(4):368–376

    Article  PubMed  CAS  Google Scholar 

  • Jimenez-Del-Rio M, Velez-Pardo C (2004a) The hydrogen peroxide and its importance in the Alzheimer’s and Parkinson’s disease. Curr Med Chem Cent Nerv Syst Agents 4:279–285

    Article  Google Scholar 

  • Jimenez-Del-Rio M, Velez-Pardo C (2004b) Transition metals-induced apoptosis in lymphocytes via hydroxyl radical generation, mitochondria dysfunction and caspase-3 activation: an in vitro model for neurodegeneration. Arch Med Res 35:185–193

    Article  PubMed  CAS  Google Scholar 

  • Jimenez-Del-Rio M, Guzman-Martinez C, Velez-Pardo C (2010) The effects of polyphenols on survival and locomotor activity in Drosophila melanogaster exposed to iron and paraquat. Neurochem Res 35:227–238

    Article  PubMed  CAS  Google Scholar 

  • Kaler SG (2011) ATP7A-related copper transport diseases—emerging concepts and future trends. Nat Rev Neurol 7(1):15–29

    Article  PubMed  CAS  Google Scholar 

  • Kosta P, Argyropoulou MI, Markoula S, Konitsiotis S (2006) MRI evaluation of the basal ganglia size and iron content in patients with Parkinson’s disease. J Neurol 253(1):26–32

    Article  PubMed  Google Scholar 

  • Lee DW, Andersen JK (2010) Iron elevations in the aging Parkinsonian brain: a consequence of impaired iron homeostasis? J Neurochem 112(2):332–339

    Article  PubMed  CAS  Google Scholar 

  • Mao Z, Davis RL (2009) Eight different types of dopaminergic neurons innervate the Drosophila mushroom body neuropil: anatomical and physiological heterogeneity. Front Neural Circuits 3:5

    Article  PubMed  Google Scholar 

  • Martin WR, Wieler M, Gee M (2008) Midbrain iron content in early Parkinson disease: a potential biomarker of disease status. Neurology 70(16 Pt 2):1411–14117

    Article  PubMed  CAS  Google Scholar 

  • Meenakshi-Sundaram S, Mahadevan A, Taly AB, Arunodaya GR, Swamy HS, Shankar SK (2008) Wilson’s disease: a clinico-neuropathological autopsy study. J Clin Neurosci 15(4):409–417

    Article  PubMed  CAS  Google Scholar 

  • Missirlis F, Holmberg S, Georgieva T, Dunkov BC, Rouault TA, Law JH (2006) Characterization of mitochondrial ferritin in Drosophila. Proc Natl Acad Sci USA 103(15):5893–5898

    Article  PubMed  CAS  Google Scholar 

  • Morello M, Zatta P, Zambenedetti P, Martorana A, D’Angelo V, Melchiorri G, Bernardi G, Sancesario G (2007) Manganese intoxication decreases the expression of manganoproteins in the rat basal ganglia: an immunohistochemical study. Brain Res Bull 74(6):406–415

    Article  PubMed  CAS  Google Scholar 

  • Muckenthaler M, Gunkel N, Frishman D, Cyrklaff A, Tomancak P, Hentze MW (1998) Iron-regulatory protein-1 (IRP-1) is highly conserved in two invertebrate species—characterization of IRP-1 homologues in Drosophila melanogaster and Caenorhabditis elegans. Eur J Biochem 254(2):230–237

    Article  PubMed  CAS  Google Scholar 

  • Nakatsuka I, Maeda S, Andoh T, Hayashi Y, Mizuno R, Higuchi H, Miyawaki T (2009) Oxidative changes in the rat brain by intraperitoneal injection of ferric nitrilotriacetate. Redox Rep 14(3):109–114

    Article  PubMed  CAS  Google Scholar 

  • Oakley AE, Collingwood JF, Dobson J, Love G, Perrott HR, Edwardson JA, Elstner M, Morris CM (2007) Individual dopaminergic neurons show raised iron levels in Parkinson disease. Neurology 68(21):1820–1825

    Article  PubMed  CAS  Google Scholar 

  • Olanow CW, Good PF, Shinotoh H, Hewitt KA, Vingerhoets F, Snow BJ, Beal MF, Calne DB, Perl DP (1996) Manganese intoxication in the rhesus monkey: a clinical, imaging, pathologic, and biochemical study. Neurology 46(2):492–498

    PubMed  CAS  Google Scholar 

  • Ordoñez-Librado JL, Anaya-Martínez V, Gutierrez-Valdez AL, Colín-Barenque L, Montiel-Flores E, Avila-Costa MR (2010) Manganese inhalation as a Parkinson disease model. Parkinsons Dis 2011:612989

    PubMed  Google Scholar 

  • Ozcelik D, Uzun H (2009) Copper intoxication; antioxidant defenses and oxidative damage in rat brain. Biol Trace Elem Res 127(1):45–52

    Article  PubMed  CAS  Google Scholar 

  • Péran P, Cherubini A, Assogna F, Piras F, Quattrocchi C, Peppe A, Celsis P, Rascol O, Démonet JF, Stefani A, Pierantozzi M, Pontieri FE, Caltagirone C, Spalletta G, Sabatini U (2010) Magnetic resonance imaging markers of Parkinson’s disease nigrostriatal signature. Brain 133(11):3423–3433

    Article  PubMed  Google Scholar 

  • Perl DP, Olanow CW (2007) The neuropathology of manganese-induced Parkinsonism. J Neuropathol Exp Neurol 66(8):675–682

    Article  PubMed  CAS  Google Scholar 

  • Pienaar IS, Götz J, Feany MB (2010) Parkinson’s disease: insights from non-traditional model organisms. Prog Neurobiol 92(4):558–571

    Article  PubMed  CAS  Google Scholar 

  • Prabhakaran K, Ghosh D, Chapman GD, Gunasekar PG (2008) Molecular mechanism of manganese exposure-induced dopaminergic toxicity. Brain Res Bull 76(4):361–367

    Article  PubMed  CAS  Google Scholar 

  • Rao KV, Norenberg MD (2004) Manganese induces the mitochondrial permeability transition in cultured astrocytes. J Biol Chem 279(31):32333–32338

    Article  PubMed  CAS  Google Scholar 

  • Reddy PV, Rao KV, Norenberg MD (2008) The mitochondrial permeability transition, and oxidative and nitrosative stress in the mechanism of copper toxicity in cultured neurons and astrocytes. Lab Invest 88(8):816–830

    Article  PubMed  CAS  Google Scholar 

  • Salazar J, Mena N, Hunot S, Prigent A, Alvarez-Fischer D, Arredondo M, Duyckaerts C, Sazdovitch V, Zhao L, Garrick LM, Nuñez MT, Garrick MD, Raisman-Vozari R, Hirsch EC (2008) Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson’s disease. Proc Natl Acad Sci USA 105(47):18578–18583

    Article  PubMed  CAS  Google Scholar 

  • Salvador GA, Uranga RM, Giusto NM (2010) Iron and mechanisms of neurotoxicity. Int J Alzheimers Dis 2011:720658

    PubMed  Google Scholar 

  • Sengstock GJ, Olanow CW, Menzies RA, Dunn AJ, Arendash GW (1993) Infusion of iron into the rat substantia nigra: nigral pathology and dose-dependent loss of striatal dopaminergic markers. J Neurosci Res 35(1):67–82

    Article  PubMed  CAS  Google Scholar 

  • Sengstock GJ, Olanow CW, Dunn AJ, Barone S Jr, Arendash GW (1994) Progressive changes in striatal dopaminergic markers, nigral volume, and rotational behavior following iron infusion into the rat substantia nigra. Exp Neurol 130(1):82–94

    Article  PubMed  CAS  Google Scholar 

  • Shinotoh H, Snow BJ, Hewitt KA, Pate BD, Doudet D, Nugent R, Perl DP, Olanow W, Calne DB (1995) MRI and PET studies of manganese-intoxicated monkeys. Neurology 45(6):1199–1204

    PubMed  CAS  Google Scholar 

  • Snyder AM, Connor JR (2009) Iron, the substantia nigra and related neurological disorders. Biochim Biophys Acta 1790(7):606–614

    Article  PubMed  CAS  Google Scholar 

  • Southon A, Farlow A, Norgate M, Burke R, Camakaris J (2008) Malvolio is a copper transporter in Drosophila melanogaster. J Exp Biol 211(Pt 5):709–716

    Article  PubMed  CAS  Google Scholar 

  • Southon A, Palstra N, Veldhuis N, Gaeth A, Robin C, Burke R, Camakaris J (2010) Conservation of copper-transporting P(IB)-type ATPase function. Biometals 23(4):681–694

    Article  PubMed  CAS  Google Scholar 

  • Spadoni F, Stefani A, Morello M, Lavaroni F, Giacomini P, Sancesario G (2000) Selective vulnerability of pallidal neurons in the early phases of manganese intoxication. Exp Brain Res 135(4):544–551

    Article  PubMed  CAS  Google Scholar 

  • Sriram K, Lin GX, Jefferson AM, Roberts JR, Chapman RS, Chen BT, Soukup JM, Ghio AJ, Antonini JM (2010) Dopaminergic neurotoxicity following pulmonary exposure to manganese-containing welding fumes. Arch Toxicol 84(7):521–540

    Article  PubMed  CAS  Google Scholar 

  • Südmeyer M, Saleh A, Wojtecki L, Cohnen M, Gross J, Ploner M, Hefter H, Timmermann L, Schnitzler A (2006) Wilson’s disease tremor is associated with magnetic resonance imaging lesions in basal ganglia structures. Mov Disord 21(12):2134–2139

    Article  PubMed  Google Scholar 

  • Takanashi M, Mochizuki H, Yokomizo K, Hattori N, Mori H, Yamamura Y, Mizuno Y (2001) Iron accumulation in the substantia nigra of autosomal recessive juvenile Parkinsonism (ARJP). Parkinsonism Relat Disord 7(4):311–314

    Article  PubMed  Google Scholar 

  • Taylor RM, Chen Y, Dhawan A, EuroWilson Consortium (2009) Triethylene tetramine dihydrochloride (trientine) in children with Wilson disease: experience at King’s College Hospital and review of the literature. Eur J Pediatr 168(9):1061–1068

    Article  PubMed  Google Scholar 

  • Tiklová K, Senti KA, Wang S, Gräslund A, Samakovlis C (2010) Epithelial septate junction assembly relies on melanotransferrin iron binding and endocytosis in Drosophila. Nat Cell Biol 12(11):1071–1077

    Article  PubMed  Google Scholar 

  • Wallis LI, Paley MN, Graham JM, Grünewald RA, Wignall EL, Joy HM, Griffiths PD (2008) MRI assessment of basal ganglia iron deposition in Parkinson’s disease. J Magn Reson Imaging 28(5):1061–1067

    Article  PubMed  Google Scholar 

  • Yoshiga T, Georgieva T, Dunkov BC, Harizanova N, Ralchev K, Law JH (1999) Drosophila melanogaster transferrin. Cloning, deduced protein sequence, expression during the life cycle, gene localization and up-regulation on bacterial infection. Eur J Biochem 260(2):414–420

    Article  PubMed  CAS  Google Scholar 

  • Youdim MB, Fridkin M, Zheng H (2004) Novel bifunctional drugs targeting monoamine oxidase inhibition and iron chelation as an approach to neuroprotection in Parkinson’s disease and other neurodegenerative diseases. J Neural Transm 111(10–11):1455–1471

    Article  PubMed  CAS  Google Scholar 

  • Yu WR, Jiang H, Wang J, Xie JX (2008) Copper (Cu2+) induces degeneration of dopaminergic neurons in the nigrostriatal system of rats. Neurosci Bull 24(2):73–78

    Article  PubMed  CAS  Google Scholar 

  • Zecca L, Stroppolo A, Gatti A, Tampellini D, Toscani M, Gallorini M, Giaveri G, Arosio P, Santambrogio P, Fariello RG, Karatekin E, Kleinman MH, Turro N, Hornykiewicz O, Zucca FA (2004) The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. Proc Natl Acad Sci USA 101(26):9843–9848

    Article  PubMed  CAS  Google Scholar 

  • Zecca L, Berg D, Arzberger T, Ruprecht P, Rausch WD, Musicco M, Tampellini D, Riederer P, Gerlach M, Becker G (2005) In vivo detection of iron and neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage. Mov Disord 20(10):1278–1285

    Article  PubMed  Google Scholar 

  • Zhang J, Zhang Y, Wang J, Cai P, Luo C, Qian Z, Dai Y, Feng H (2010) Characterizing iron deposition in Parkinson’s disease using susceptibility-weighted imaging: an in vivo MR study. Brain Res 1330:124–130

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Colciencias grants #1115-408-20504 to CV-P and MJ-Del-Rio. LB-R is student at the Master Program in Biomedical Science (CCBB) from UdeA. We are grateful to A. Daza-Restrepo for technical assistance. We thank G. Gomez (GDCON Laboratory-SIU) for flame atomic absorption spectrometry assay from the Faculty of Engineering, UdeA.

Author information

Authors and Affiliations

  1. School of Medicine, Medical Research Institute, Neuroscience Research Group, University of Antioquia (UdeA), Calle 62 # 52-59, Building 1, Laboratory 412, SIU, Medellin, Colombia

    Leonardo Bonilla-Ramirez, Marlene Jimenez-Del-Rio & Carlos Velez-Pardo

  2. School of Medicine, Medical Research Institute, Neuroscience Research Group, University of Antioquia (UdeA), Calle 62 # 52-59, Building 1, Room 412, SIU, Medellin, Colombia

    Carlos Velez-Pardo

Authors
  1. Leonardo Bonilla-Ramirez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marlene Jimenez-Del-Rio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlos Velez-Pardo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carlos Velez-Pardo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bonilla-Ramirez, L., Jimenez-Del-Rio, M. & Velez-Pardo, C. Acute and chronic metal exposure impairs locomotion activity in Drosophila melanogaster: a model to study Parkinsonism. Biometals 24, 1045–1057 (2011). https://doi.org/10.1007/s10534-011-9463-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-011-9463-0

Keywords

Search

Navigation