Abstract
Effects of adenovirus-mediated gene transfer of glial cell line-derived neurotrophic factor (GDNF) were studied in transgenic (Tg) mice model for amyotrophic lateral sclerosis (ALS). Adenoviral vector containing GDNF gene (Ad-GDNF), E. coli lacZ (Ad-LacZ), or vehicle was injected once a week from 35 weeks of age into the right gastrocnemius muscle of Tg mice carrying mutant human Cu/Zn superoxide dismutase (SOD1) gene, and histological analysis was performed at 46 W. Clinical data showed a tendency of improvement, but was not significantly different among the three animal groups. In contrast, total number of and phospho-Akt (p-Akt) positive large motor neurons in the treated side was significantly preserved in Ad-GDNF-treated group than in vehicle- and Ad-LacZ-treated groups (*p < 0.05). Immunoreactivity of phospho-ERK (p-ERK) and active caspases-3 and -9 showed no difference. These results indicate that the Ad-GDNF treatment prevented motor neuron loss with preserving survival p-Akt signal and without affecting caspase activations, suggesting a future possibility for the therapy of the disease.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Deng HX, Hentati A, Tainer JA, et al Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science 1993; 261: 1047-1105.
Abe K, Pan L-H, Watanabe M, Kato T, Itoyama Y Induction of nitrotyrosine-like immunoreactivity in the lower motor neuron of amyotrophic lateral sclerosis. Neurosci Lett 1995; 199: 152-154.
Manabe Y, Wang JM, Warita H, et al Glutamate enhances DNA fragmentation in cultured spinal motor neurons of rat. Neurol Res 2001; 23: 79-82.
Manabe Y, Wang JM, Murakami T, et al Expressions of nitrotyrosine and TUNEL immunoreactivities in cultured rat spinal cord neurons after exposure to glutamate, nitric oxide, or peroxynitrite. J Neurosci Res 2001; 65: 371-377.
Ferrante RL, Browne SE, Shinobu LA, et al Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem 1997; 69: 2064-2074.
Manabe Y, Wang JM, Warita H, Shiro Y, Abe K Expressions of caspase-3,TUNEL,and HSP72 immunoreactivities in cultured spinal cord neurons of rat after exposure to glutamate, nitric oxide, or peroxynitrite. Neurotox Res 2001; 3: 281-289.
Manabe Y, Warita H, Murakami T, et al Early decrease of redox factor-1 in spinal motor neurons of presymptomatic transgenic mice with a mutnat SOD1 gene. Brain Res 2001; 915: 104-107.
Durham HD, Roy J, Dong L, Figlewicz DA Aggregation of mutant Cu/Zn superoxide dismutase proteins in a culture model of ALS. J Neuropathol Exp Neurol 1997; 56: 523-530.
Warita H, Manabe Y, Murakami Y, et al Early decrease of survival signal-related proteins in spinal motor neurons of presymptomatic transgenic mice with a mutant SOD1 gene. Apoptosis 2001; 6: 345-352.
Gurney ME, Pu H, Chiu AY, et al Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 1994; 264: 1772-1775.
Mitsumoto H, Ikeda K, Klinkosz B, et al Arrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF. Science 1994; 265: 1107-1110.
Oppenheim RW, Houenou LJ, Johnson JE, et al Developing motor neurons rescued from programmed and axotomyinduced cell death by GDNF. Nature 1995; 373: 344-346.
Munson JB, McMahon SB Effects of GDNF on axotomized sensory and motor neurons in adults rats. Eur J Neurosci 1997; 9: 1126-1129.
Henderson CE, Phillips HS, Pollock RA, et al GDNF:Apotent survival factor for motoneurons present in peripheral nerve and muscle. Science 1994; 266: 1062-1064.
Bordet T, Schmalbruch H, Pettmann B, et al Adenoviral cardiotrophin-1 gene transfer protects pmn mice from progressive motor neuropathy. J Clin Invest 1999; 104: 1077-1085.
Abe K, Setoguchi Y, Hayashi T, Itoyama Y In vivo adenovirusmediated gene transfer and the expression in ischemic and reperfused rat brain. Brain Res 1997; 763: 191-201.
Warita H, Abe K, Setoguchi Y, Itoyama Y Expression of adenovirus-mediated E. coli lacZ gene in skeletal muscles and spinal motor neurons of transgenic mice with a mutant superoxide dismutase gene. Neurosci Lett 1998; 246: 153-156.
Setoguchi Y, Danel C, Crystal RG Stimulation of erythropoiesis by in vivo gene theraphy: Physiologic consequences of transfer of the human erythropoietin gene to experimental animals using an adenovirus vector. Blood 1994; 84: 2946-2953.
Kitagawa H, Sasaki C, Sakai K, et al Adenovirus-mediated gene transfer of glial cell line-derived neurotrophic factor prevents ischemic brain injyury after transient middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab 1999; 19: 1336-1344.
Warita H, Itoyama Y, Abe K Selective impairment of fast anterograde axonal transport in the peripheral nerves of asymptomatic transgenic mice with a G93A mutant SOD1 gene. Brain Res 1999; 819: 120-131.
Abe K, Morita S, Kikuchi T, Itoyama Y Protective effect of a novel free radical scavenger, OPC-14117, on wobbler mouse motor neuron disease. J Neurosci Res 1997; 48: 63-70.
Warita H, Hayashi T, Murakami T, Manabe Y, Abe K Oxidative damage to mitochondrial DNA in spinal motoneurons of transgenic ALS mice. Mol Brain Res 2001; 89: 147-152.
Haase G, Kunnel P, Pettman B, et al Gene therapy of murine motor neuron disease using adenoviral vectors for neurotrophic factors. Nat Med 1997; 3: 429-436.
Mahajeri MH, Figlewicz DA, Bohn MC Intramuscular grafts of myoblasts genetically modified to secrete glial cell linederived neurotrophic factor prevent motoneuron loss and disease progression in a mouse model of familial amyotrophic lateral sclerosis (FALS). Hum Gene Ther 1999; 3: 1853-1866.
Dudek H, Datta SR, Franke TF, et al Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 1997; 275: 661-665.
Datta SR, Dudek H, Tao X, et al Akt phosphorylation of BAD couples survival signals to the cellintrinsic death machinery. Cell 1997; 91: 231-241.
Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, et al Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature 1997; 385: 544-548.
Sagot Y, Tan SA, Hammang JP, Aebischer P, Kato AC GDNF slows loss of motoneurons but not axonal degeneration or premature death of pmn/pmn mice. J Neurosci 1996; 16: 2335-2341.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Manabe, Y., Nagano, I., Gazi, M.S.A. et al. Adenovirus-mediated gene transfer of glial cell line-derived neurotrophic factor prevents motor neuron loss of transgenic model mice for amyotrophic lateral sclerosis. Apoptosis 7, 329–334 (2002). https://doi.org/10.1023/A:1016123413038
Issue Date:
DOI: https://doi.org/10.1023/A:1016123413038