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Hansruedi Bueler

Mechanisms of Neurodegeneration and Gene Therapy for Parkinson's Disease

Hansruedi Büeler

(START fellow)

present address:

Hansruedi Bueler, Ph.D.
Associate Professor
University of Kentucky
Chandler Medical Center
Department of Anatomy and Neurobiology
425 Health Sciences Research Building
800 Rose St.
Lexington, KY 40536-0098

Institut für Molekularbiologie
University of Zurich
Winterthurerstrasse 190
CH-8057 Zurich

phone: +41 44 63 53141 (office)
phone: +41 44 63 53181 (lab)
fax: +41 44 63 56811



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We are interested in the mechanisms underlying neurodegeneration in a number of disorders. Oxidative stress, apoptosis and exitotoxicity have been proposed as possible causes for several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease and ALS.

Our research focuses on the elucidation of the contribution of oxidative stress and apoptosis to neurodegeneration in Parkinson's disease and amyotrophic lateral sclerosis. We are studying the effects on neurodegeneration of antioxidant, anti-apoptotic and neurotrophic factors expressed in animal models of these disorders after infection with recombinant adeno-associated viruses (rAAV). A long-term goal is the development of gene therapy strategies based on rAAV-mediated expression of therapeutic genes in specific regions of neurodegeneration in the CNS. In addition, using rAAV vectors as well as knockout and transgenic mouse technologies we are investigating the function of genes involved in familial PD.

Recent publications


Dong Z, Wolfer DP, Lipp HP and Bueler H (2005) "Hsp70 gene transfer by adeno-associated virus inhibits MPTP-induced nigrostriatal degeneration in the mouse model of Parkinson disease." Mol Ther 11(1): 80-88. Abstract

Gruchala M, Bhardwaj S, Pajusola K, Roy H, Rissanen TT, Kokina I, Kholova I, Markkanen JE, Rutanen J, Heikura T, Alitalo K, Bueler H and Yla-Herttuala S (2004) "Gene transfer into rabbit arteries with adeno-associated virus and adenovirus vectors." J Gene Med 6(5): 545-554. Abstract

Paterna JC, Feldon J and Bueler H (2004) "Transduction profiles of recombinant adeno-associated virus vectors derived from serotypes 2 and 5 in the nigrostriatal system of rats." J Virol 78(13): 6808-6817. Abstract

Weissmann C and Bueler H (2004) "A mouse to remember." Cell 116(2 Suppl):S111-113, 112 p following S113 Abstract

Fraefel C, Bittermann AG, Bueler H, Heid I, Bachi T and Ackermann M (2004) "Spatial and temporal organization of adeno-associated virus DNA replication in live cells." J Virol 78(1):389-398 Abstract

Jalkanen J, Leppanen P, Pajusola K, Narvanen O, Mahonen A, Vahakangas E, Greaves DR, Bueler H and Yla-Herttuala S (2003) "Adeno-associated virus-mediated gene transfer of a secreted decoy human macrophage scavenger receptor reduces atherosclerotic lesion formation in LDL receptor knockout mice." Mol Ther 8(6):903-910 Abstract

Vassalli G, Bueler H, Dudler J, von Segesser LK and Kappenberger L (2003) "Adeno-associated virus (AAV) vectors achieve prolonged transgene expression in mouse myocardium and arteries in vivo: a comparative study with adenovirus vectors." Int J Cardiol 90(2-3):229-238 Abstract

Dong Z, Ferger B, Paterna JC, Vogel D, Furler S, Osinde M, Feldon J and Bueler H (2003) "Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1." Proc Natl Acad Sci U S A 100(21):12438-12443 Abstract

Dong Z, Ferger B, Feldon J and Bueler H (2002) "Overexpression of Parkinson's disease-associated alpha-synucleinA53T by recombinant adeno-associated virus in mice does not increase the vulnerability of dopaminergic neurons to MPTP." J Neurobiol 53(1): 1-10. Abstract

Pajusola K, Gruchala M, Joch H, Luscher TF, Yla-Herttuala S and Bueler H (2002) "Cell-type-specific characteristics modulate the transduction efficiency of adeno-associated virus type 2 and restrain infection of endothelial cells." J Virol 76(22): 11530-11540. Abstract

Paterna JC and Bueler H (2002) "Recombinant adeno-associated virus vector design and gene expression in the mammalian brain." Methods 28(2): 208-218. Abstract

Saaristo A, Veikkola T, Enholm B, Hytonen M, Arola J, Pajusola K, Turunen P, Jeltsch M, Karkkainen MJ, Kerjaschki D, Bueler H, Yla-Herttuala S and Alitalo K (2002) "Adenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes." Faseb J 16(9): 1041-1049. Abstract

Saaristo A, Veikkola T, Tammela T, Enholm B, Karkkainen MJ, Pajusola K, Bueler H, Yla-Herttuala S and Alitalo K (2002) "Lymphangiogenic gene therapy with minimal blood vascular side effects." J Exp Med 196(6): 719-730. Abstract

Ehrengruber, M.U., Hennou, S., Büeler, H., Naim, H. Y., Déglon, N., and Lundstrom, K. (2001). Gene transfer into neurons from hippocampal slices: comparison of recombinant Semliki Forest virus, adenovirus, adeno-associated virus, lentivirus, and measles virus. Mol. Cell. Neurosci, 17(5):855-71.

Furler, S., Paterna, J.-C., Weibel, M., and Büeler, H. (2001). Recombinant AAV vectors containing the foot-and-mouth-disease virus 2A sequence confer efficient bicistronic gene expression in cultured cells and rat substantia nigra neurons. Gene Therapy, 8(11):864-73.

Karkkainen MJ, Saaristo A, Jussila L, Karila KA, Lawrence EC, Pajusola K, Bueler H, Eichmann A, Kauppinen R, Kettunen MI, Yla-Herttuala S, Finegold DN, Ferrell RE, Alitalo K. (2001) A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci U S A. 98(22):12677-82.

Paterna JC, Moccetti T, Mura A, Feldon J, Bueler H.(2000). Influence of promoter and WHV post-transcriptional regulatory element on AAV-mediated transgene expression in the rat brain. Gene Ther. 2000 Aug; 7(15):1304-11.

Klein C, Büeler H, and Mulligan RC. (2000). Comparative Analysis of Genetically-Modified Dendritic Cells and Tumor Cells As Therapeutic Cancer Vaccines. J. Exp. Med. 191, 1699-1708.

Azzouz M, Hottinger A, Paterna J-C, Zurn AD, Aebischer P, and Büeler H. (2000). Increased motoneuron survival and improved neuromuscular function in transgenic ALS mice after intraspinal injection of an adeno-associated virus encoding bcl-2. Human Molecular Genetics 9, 803-811.

Glatzel M, Flechsig E, Navarro B, Klein MA, Paterna JC, Büeler H, Aguzzi A. (2000). Adenoviral and adeno-associated viral transfer of genes to the peripheral nervous system. Proc Natl Acad Sci USA 97, 442-447.

Büeler, H. (1999). Adeno-associated viral vectors for gene transfer and gene therapy. Biol. Chem. 380, 613-622.

Büeler, H., and Mulligan, R.C. (1996). Induction of antigen-specific tumor immunity by genetic and cellular vaccines against MAGE: enhanced tumor protection by coexpression of granulocyte-macrophage colony-stimulating factor and B7-1. Molecular Medicine 2, 545-555.

Weissmann, C., Fischer, M., Raeber, A., Büeler, H., Sailer, A., Shmerling, D., Rülicke, T., Brandner, S., and Aguzzi, A. (1996). The use of transgenic mice in the investigation of transmissible spongiform encephalopathies. Int. J. Exp. Path. 7777(6):283-93 (Review).

Büeler, H., Raeber, A., Sailer, A., Fischer, M., and Weissmann, C. (1994). High prion and PrPSc levels but delayed onset of disease in scrapie-inoculated mice heterozygous for a disrupted PrP gene. Molecular Medicine 1, 19-30.

Sailer, A., Büeler, H., Fischer, M., Aguzzi, A., and Weissmann, C. (1994). No propagation of prions in mice devoid of PrP. Cell 77, 967-968.

Weissmann, C., Büeler, H., Fischer, M., Sailer, A., Aguzzi, A., and Aguet, M. (1994). PrP-deficient mice are resistant to scrapie. Ann N Y Acad Sci 724, 235-240.

Büeler, H., Aguzzi, A., Sailer, A., Greiner, R. A., Autenried, P., Aguet, M., and Weissmann, C. (1993). Mice devoid of PrP are resistant to scrapie. Cell 73, 1339-47.

Moser, M., Oesch, B., and Büeler, H. (1993). An anti-prion protein? [letter]. Nature 362, 213-4.

Weissmann, C., Büeler, H., Sailer, A., Fischer, M., Aguet, M., and Aguzzi, A. (1993). Role of PrP in prion diseases. Br Med Bull 49, 995-1011.

Weissmann, C., Büeler, H., Fischer, M., and Aguet, M. (1993). Role of the PrP gene in transmissible spongiform encephalopathies. In "Viruses and virus-like agents in disease, (R. M. Zinkernagel and W. Stauffacher, eds.). Karger Basel. Intervirology 35, 164-75.

Weissmann, C., Büeler, H., Fischer, M., and Aguet, M. (1993). The PrP-less mouse: a tool for prion research. In "Transgenic Animals as Model Systems for Human Diseases". Schering Foundation Workshop 6 (E. F. Wagner, F. Theuring, eds.). Springer Verlag, pp. 39-56.

Büeler, H., Fischer, M., Lang, Y., Bluethmann, H., Lipp, H. P., De Armond, S. J., Prusiner, S. B., Aguet, M., and Weissmann, C. (1992). Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein [see comments]. Nature 356, 577-82.

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