Direct MRI-guided stereotaxic viral mediated gene transfer of alpha-synuclein in the Gottingen minipig CNS

• Autorzy: Glud A.N. , Hedegaard C. , Nielsen M. S. , Sorensen J. C. , Bendixen C. , Jensen P. H. , Mogensen P. H. , Larsen K. , Bjarkam C. R.
• Języki publikacji: EN

Abstrakty

EN

The aim was to establish a non-primate large animal PD model by lentiviral vector mediated mutant alpha-synuclein overexpression in the substantia nigra. Lentivirus encoding A53T alpha-synuclein (6 x 2.5 ^l) was stereotaxically injected into the substantia nigra of six adult female Gottingen minipigs. Contralateral control injections encoding enhanced green fluorescent protein (EGFP) were performed. Gait-analysis was performed pre- and postoperatively. PCR of the transgenes and immunohistochemical staining against alpha-synuclein, EGFP, GFAP and TH was performed after 20 weeks. Gait- analysis revealed a significant increase in step length and height, and a decrease in the double stand phase. PCR verified the mesencephalic presence of transgenes. IHC analysis showed alpha-synuclein expression in nigral neurons, around the injection tract and in related nigrostriatal projections. The alpha-synuclein positive neurons appeared swollen and vacuolated, in contrast to the EGFP-injected control side. To transduct all nigrostriatal cells with few microinjections, wider dissemination of the transgene must be achieved.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2011
• Tom: 71
• Numer: 4
• Opis fizyczny: p.508-518,fig.,ref.

Twórcy

autor

Glud A.N.

• Institute of Biomedicine, Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
• Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark

autor

Hedegaard C.

• Department of Genetics and Biotechnology, Faculty of Agricultural Sciences, University of Aarhus, Tjele, Denmark

autor

Nielsen M. S.

• Institute of Biomedicine, Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark

autor

Sorensen J. C.

• Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark

autor

Bendixen C.

• Department of Genetics and Biotechnology, Faculty of Agricultural Sciences, University of Aarhus, Tjele, Denmark

autor

Jensen P. H.

• Institute of Biomedicine, Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark

autor

Mogensen P. H.

• Hammel Neurorehabilitation Centre, Hamme, Denmark

autor

Larsen K.

• Department of Genetics and Biotechnology, Faculty of Agricultural Sciences, University of Aarhus, Tjele, Denmark

autor

Bjarkam C. R.

• Institute of Biomedicine, Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
• Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark

Bibliografia

• Aebischer P, Ridet JL (2001) Recombinant proteins for neu­rodegenerative diseases: the delivery issue. Trends Neurosci 24: 533-540.
• Andersen F, Watanabe H, Bjarkam C, Danielsen EH, Cumming P; DaNeX Study Group (2005) Pig brain ste­reotaxic standard space: mapping of cerebral blood flow normative values and effect of MPTP-lesioning. Brain Res Bull 66: 17-29.
• Bayer TA, Jäkälä P, Hartmann T, Havas L, McLean C, Culvenor JG, Li QX, Masters CL, Falkai P, Beyreuther K (1999) Alpha-synuclein accumulates in Lewy bodies in Parkinson's disease and dementia with Lewy bodies but not in Alzheimer's disease beta-amyloid plaque cores. Neurosci Lett 266: 213-216.
• Bjarkam CR, Cancian G, Nielsen M, Rosendahl, F Ettrup K, Zeidler D (2004) A MRI-compatible stereotaxic localizer box enables high-precision stereotaxic procedures in pigs. J Neurosci Meth 139: 293-298.
• Bjarkam CR, Larsen M, Watanabe H, Röhl L,Simonsen CZ, Pedersen M, Ringgaard S, Andersen F, Cumming P, Dalmose AL, M0ller A, Jensen LW, Danielsen EH, Dalmau I, Finsen B, Öttingen Gv, Gjedde A, S0rensen JC (2005) A porcine model of subthalamic high-frequency deep brain stimulation in Parkinson's disease. In: Parkinson's Disease: New Research (Willow MJ, ed.). Nova Science Publishers, New York, NY.
• Bjarkam CR, Nielsen MS, Glud AN, Rosendal F, Mogensen P, Bender D, Doudet D, M0ller A, S0rensen JC (2008) Neuromodulation in a minipig MPTP model of Parkinson disease. Br J Neurosurg 22 (Suppl): S9-12.
• Bjarkam CR, Cancian G, Glud AN, Ettrup KS, J0rgensen RL, S0rensen JC (2009) MRI-guided stereotaxic tar­geting in pigs based on a stereotaxic localizer box fitted with an isocentric frame and use of SurgiPlan computer-planning software. J Neurosci Methods 183: 119-126.
• Bjarkam CR, Glud AN, Margolin L, Reinhart K, Franklin R, Deding D, Ettrup KS, Fitting LM, Nielsen MS, S0rensen JC, Cunningham MG (2010) Safety and func­tion of a new clinical intracerebral microinjection instrument (IMI) for stem cells and therapeutics exam­ined in the Göttingen minipig. Stereotact Funct Neurosurg 88: 56-63.
• Bjerre D, Madsen LB, Bendixen C, Larsen K (2006) Porcine Parkin: molecular cloning of PARK2 cDNA, expression analysis, and identification of a splicing variant. Biochem Biophys Res Commun 347: 803-813.
• Blomer, U, Naldini L, Kafri T, Trono D, Verma IM, Gage FH (1997) Highly efficient and sustained gene transfer in adult neurons with a lentivirus vector. J Virol 71: 6641­6649.
• Capitanio JP, Emborg ME (2008) Contributions of non-hu­man primates to neuroscience research. Lancet 371: 1126-1235
• Cearley CN, Wolfe JH (2007) A single injection of an adeno- associated virus vector into nuclei with divergent connec­tions results in widespread vector distribution in the brain and global correction of a neurogenetic disease. J Neurosci 27: 9928-9940.
• Cumming P, Danielsen EH, Vafaee M, Falborg L, Steffensen E, S0rensen JC, Gillings N, Bender D, Marthi K, Andersen F, Munk O, Smith D, M0ller A, Gjedde A (2001) Normalization of markers for dopamine innerva­tion in striatum of MPTP-lesioned miniature pigs with intrastriatal grafts. Acta Neurol Scand 103: 309-315.
• Cumming P, Gillings NM, Jensen SB, Bjarkam C, Gjedde A (2003) Kinetics of the uptake and distribution of the dop­amine D(2,3) agonist (R)-N-[1-(11)C]n-propylnorapo- morphine in brain of healthy and MPTP-treated Göttingen miniature pigs. Nucl Med Biol 30: 547-553.
• Dalmose AL, Bjarkam CR, S0rensen JC, Djurhuus JC, J0rgensen TM (2004) Effects of high frequency deep brain stimulation on urine storage and voiding function in conscious minipigs. Neurourol Urodyn 23: 265-272.
• Dalmose AL, Bjarkam CR, Djurhuus JC (2005) Stereotactic electrical stimulation of the pontine micturition centre in the pig. BJU Int 95: 886-889.
• Danielsen EH, Smith DF, Poulsen PH, 0stergaard L, Gee A, Ishizu K, Venkatachalam TK, Bender D, Hansen S, Gjedde A, Scheel-Krüger J, Maller A (1998) Positron emission tomography of living brain in minipigs and domestic pigs. Scand J Lab Anim Sci Suppl 25: 127-135.
• Danielsen EH, Cumming P, Andersen F, Bender D, Brevig T, Falborg L, Gee A, Gillings NM, Hansen SB, Hermansen F, Johansen J, Johansen TE, Dahl-J0rgensen A, J0rgensen HA, Meyer M, Munk O, Pedersen EB, Poulsen PH, Rodell AB, Sakoh M, Simonsen CZ, Smith DF, S0rensen JC, Ostergärd L, Zimmer J, Gjedde A, M0ller A (2000) The DaNeX study of embryonic mesencephalic, dop­aminergic tissue grafted to a minipig model of Parkinson's disease: preliminary findings of effect of MPTP poison­ing on striatal dopaminergic markers. Cell Transplant 9: 247-259.
• Danielsen EH, Smith D, Hermansen F, Gjedde A, Cumming P (2001) Acute neuroleptic stimulates DOPA decarboxy­lase in porcine brain in vivo. Synapse 41: 172-175.
• Davidson BL, Breakefield XO (2003) Viral vectors for gene delivery to the nervous system. Nat Rev Neurosci 4: 353-364.
• Dawson TM, Ko HS, Dawson VL (2010) Genetic animal models of Parkinson's disease. Neuron 66: 646-661.
• Ettrup KS, S0rensen JC, Bjarkam CR (2010) The anatomy ofthe Göttingen minipig hypothalamus. J Chem Neuroanat 39: 151-165.
• Fjord-Larsen L, Kusk P, Torrnae J, Juliusson B, Torp M, Bjarkam CR, Nielsen MS, Handberg A, S0rensen JC, Wahlberg LU (2010) Long-term delivery of nerve growth factor by encapsulated cell biodelivery in the Göttingen minipig basal forebrain, Mol Ther 18: 2164-2172.
• Glud AN, Hedegaard C, Nielsen MS, S0rensen JC, Bendixen C, Jensen PH, Larsen K, Bjarkam CR (2010) Direct gene transfer in the Gottingen minipig CNS using stereotaxic lentiviral microinjections. Acta Neurobiol Exp (Wars) 70: 308-315.
• Goodman S, Check E (2002) The great primate debate. Nature 417: 684-687.
• Jenner P (2009) From the MPTP-treated primate to the treat­ment of motor complications in Parkinson's disease. Parkinsonism Relat Disord 15 (Suppl 4): S18-23.
• Jensen KN, Deding D, S0rensen JC, Bjarkam CR (2009) Long-term implantation of deep brain stimulation elec­trodes in the pontine micturition centre of the Göttingen minipig. Acta Neurochir (Wien) 151: 785-794.
• Langston JW, Forno LS, Rebert CS, Irwin I (1984) Selective nigral toxicity after systemic administration of 1-methyl- 4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey. Brain Res 292: 390-394.
• Larsen M, Bjarkam CR, 0stergaard K, West M, Sorensen JC (2004) The anatomy of the porcine subthalamic nucleus evaluated with immunohistochemistry and design-based stereology. Anat Embryol 208: 239-247.
• Lewis P, Hensel M, Emerman M (1992) Human immunode­ficiency virus infection of cells arrested in the cell cycle. EMBO J 11: 3053-3058.
• Meredith GE, Sonsalla PK, Chesselet MF (2008) Animal models of Parkinson's disease progression. Acta Neuropathol 115: 385-398.
• Mikkelsen M, M0ller A, Jensen LH, Pedersen A, Harajehi JB, Pakkenberg H (1999) MPTP-induced Parkinsonism in minipigs: A behavioral, biochemical, and histological study. Neurotoxicol Teratol 21: 169-175.
• Naldini L, Blömer U, Gallay P, Ory D, Mulligan R, Gage FH, Verma IM, Trono D (1996) In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272: 263-267.
• Naldini L (1998) Lentiviruses as gene transfer agents for delivery to non-dividing cells. Curr Opin Biotechnol 9: 457-463.
• Nielsen MS, S0rensen JC, Bjarkam CR (2009) The substan­tia nigra pars compacta of the Göttingen minipig: an anatomical and stereological study. Brain Struct Funct 213: 481-488.
• Olsen AKA (2010) Anesthesia and Annalgesia in Ellegaard Göttingen Minipigs. Ellegaard, SE.
• Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1998) Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276: 2045-2047.
• Ralph SG, Bilney K, Wong L-F, Azzouz M, Mazarakis ND (2006) Gene therapy for neurodegenerative and ocular diseases using lentiviral vectors, Clin Sci 110: 37-46.
• Rosendal F, Bjarkam CR, Larsen M, Hansen HE, Madsen M, S0rensen JC, Mortensen J (2005) Does chronic low- dose treatment with cyclosporine influence the brain? A histopathological study in pigs. Transplant Proc 37: 3305-3308.
• Rosendal F, Pedersen M, Sangill R, St0dkilde-J0rgensen H, Nielsen MS, Bjarkam CR, Sunde N, S0rensen JC, (2009) MRI protocol for in vivo visualization of the Göttingen minipig brain improves targeting in experimental func­tional neurosurgery. Brain Res Bull 79: 41-45.
• R0hl L, Sakoh M, Simonsen CZ, Vestergaard-Poulsen P, Sangill R, S0rensen JC, Bjarkam CR, Gyldensted C, 0stergaard L (2002) Time evolution of cerebral perfusion and apparent diffusion coefficient measured by magnetic resonance imaging in a porcine stroke model. J Magn Reson Imaging 15: 123-129.
• Salvatore MF, Ai Y, Fischer B, Zhang AM, Grondin RC, Zhang Z, Gerhardt GA, Gash DM (2006) Point source concentration of GDNF may explain failure of phase II clinical trial. Exp Neurol 202: 497-505.
• S0rensen JC, Bjarkam CR, Danielsen EH, Simonsen CZ, Geneser FA (2000) Oriented sectioning of irregular tissue blocks in relation to computerized scanning modalities: results from the domestic pig brain. J Neurosci Methods 104: 93-98.
• Terzioglu M, Galter D (2008) Parkinson's disease: genetic versus toxin-induced rodent models. FEBS J 275: 1384­1391.
• Thomas CE, Ehrhardt A, Kay MA (2003) Progress and prob­lems with the use of viral vectors for gene therapy. Nat Rev Genet 4: 346-358.
• Trono D (2000) Lentiviral vectors: turning a deadly foe into a therapeutic agent. Gene Ther 7: 20-23.
• Verma IM, Somia N (1997) Gene therapy - promises, prob­lems and prospects. Nature 389: 239-242.
• Watanabe H, Andersen F, Simonsen CZ, Evans SM, Gjedde A, Cumming P, DaNeX Study Group (2001) MR-based statistical atlas of the Gottingen minipig brain. Neuroimage 14: 1089-1096.

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