Abstract
Glial cell line-derived neurotrophic factor (GDNF) is a strong candidate agent in the neuroprotective treatment of Parkinson's disease (PD). We investigated whether adeno-associated viral (AAV) vector-mediated delivery of a GDNF gene in a delayed manner could prevent progressive degeneration of dopaminergic (DA) neurons, while preserving a functional nigrostriatal pathway. Four weeks after a unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA), rats received injection of AAV vectors expressing GDNF tagged with FLAG peptide (AAV-GDNFflag) or β-galactosidase (AAV-LacZ) into the lesioned striatum. Immunostaining for FLAG demonstrated retrograde transport of GDNFflag to the substantia nigra (SN). The density of tyrosine hydroxylase (TH)-positive DA fibers in the striatum and the number of TH-positive or cholera toxin subunit B (CTB, neuronal tracer)-labeled neurons in the SN were significantly greater in the AAV-GDNFflag group than in the AAV-LacZ group. Dopamine levels and those of its metabolites in the striatum were remarkably higher in the AAV-GDNFflag group compared with the control group. Consistent with anatomical and biochemical changes, significant behavioral recovery was observed from 4–20 weeks following AAV-GDNFflag injection. These data indicate that a delayed delivery of GDNF gene using AAV vector is efficacious even 4 weeks after the onset of progressive degeneration in a rat model of PD.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Dunnett S.B., Bjorklund A. . Prospects for new restorative and neuroprotective treatments in Parkinson's disease Nature 1999 399: A32 A32
Bjorklund A. et al. Towards a neuroprotective gene therapy for Parkinson's disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model Brain Res 2000 886: 82 82
Bohn M.C. . Parkinson's disease: a neurodegenerative disease particularly amenable to gene therapy Mol Ther 2000 1: 494 494
Ozawa K. et al. Gene therapy of Parkinson's disease using adeno-associated virus (AAV) vectors J Neural Transm Suppl 2000 58: 181 181
Choi-Lundberg D.L. et al. Dopaminergic neurons protected from degeneration by GDNF gene therapy Science 1997 275: 838 838
Mandel R.J., Spratt S.K., Snyder R.O., Leff S.E. . Midbrain injection of recombinant adeno-associated virus encoding rat glial cell line-derived neurotrophic factor protects nigral neurons in a progressive 6-hydroxydopamine-induced degeneration model of Parkinson's disease in rats Proc Natl Acad Sci USA 1997 94: 14083 14083
Bilang-Bleuel A. et al. Intrastriatal injection of an adenoviral vector expressing glial cell line-derived neurotrophic factor prevents dopaminergic neuron degeneration and behavioral impairment in a rat model of Parkinson disease Proc Natl Acad Sci USA 1997 94: 8818 8818
Choi-Lundberg D.L. et al. Behavioral and cellular protection of rat dopaminergic neurons by an adenoviral vector encoding glial cell line-derived neurotrophic factor Exp Neurol 1998 154: 261 261
Mandel R.J., Snyder R.O., Leff S.E. . Recombinant adeno-associated viral vector-mediated glial cell line-derived neurotrophic factor gene transfer protects nigral dopamine neurons after onset of progressive degeneration in a rat model of Parkinson's disease Exp Neurol 1999 160: 205 205
Kirik D., Rosenblad C., Bjorklund A., Mandel R.J. . Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson's model: intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system J Neurosci 2000 20: 4686 4686
Bensadoun J.C. et al. Lentiviral vectors as a gene delivery system in the mouse midbrain: cellular and behavioral improvements in a 6-OHDA model of Parkinson's disease using GDNF Exp Neurol 2000 164: 15 15
Kordower J.H. et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease Science 2000 290: 767 767
Leman S., Viltart O., Sequeira H. . Double immunocytochemistry for the detection of Fos protein in retrogradely identified neurons using cholera toxin B subunit Brain Res Brain Res Protoc 2000 5: 298 298
Monahan P.E., Samulski R.J. . AAV vectors: is clinical success on the horizon? Gene Therapy 2000 7: 24 24
Bankiewicz K.S. et al. Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach Exp Neurol 2000 164: 2 2
Shen Y. . Triple transduction with adeno-associated virus vectors expressing tyrosine hydroxylase aromatic-L-amino-acid decarboxylase and GTP cyclohydrolase I for gene therapy of Parkinson's disease Hum Gene Ther 2000 11: 1509 1509
Sauer H., Oertel W.H. . Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat Neuroscience 1994 59: 401 401
Hudson J.L. et al. Correlation of apomorphine- and amphetamine-induced turning with nigrostriatal dopamine content in unilateral 6-hydroxydopamine lesioned rats Brain Res 1993 626: 167 167
Javoy-Agid F. et al. Decreased tyrosine hydroxylase messenger RNA in the surviving dopamine neurons of the substantia nigra in Parkinson's disease: an in situ hybridization study Neuroscience 1990 38: 245 245
Fearnley J.M., Lees A.J. . Ageing and Parkinson's disease: substantia nigra regional selectivity Brain 1991 114: 2283 2283
Schulzer M. et al. A mathematical model of pathogenesis in idiopathic parkinsonism Brain 1994 117: 509 509
Kozlowski D.A. et al. Delivery of a GDNF gene into the substantia nigra after a progressive 6-OHDA lesion maintains functional nigrostriatal connections Exp Neurol 2000 166: 1 1
Connor B. et al. Differential effects of glial cell line-derived neurotrophic factor (GDNF) in the striatum and substantia nigra of the aged Parkinsonian rat Gene Therapy 1999 6: 1936 1936
Winkler C., Sauer H., Lee C.S., Bjorklund A. . Short-term GDNF treatment provides long-term rescue of lesioned nigral dopaminergic neurons in a rat model of Parkinson's disease J Neurosci 1996 16: 7206 7206
Natsume A. et al. Bcl-2 and GDNF delivered by HSV-mediated gene transfer act additively to protect dopaminergic neurons from 6-OHDA-induced degeneration Exp Neurol 2001 169: 231 231
Rosenblad C., Kirik D., Bjorklund A. . Sequential administration of GDNF into the substantia nigra and striatum promotes dopamine neuron survival and axonal sprouting, but not striatal reinnervation or functional recovery in the partial 6-OHDA lesion model Exp Neurol 2000 161: 503 503
McCown T.J. et al. Differential and persistent expression patterns of CNS gene transfer by an adeno-associated virus (AAV) vector Brain Res 1996 713: 99 99
Kaplitt M.G. et al. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain Nat Genet 1994 8: 148 148
Lo W.D. et al. Adeno-associated virus-mediated gene transfer to the brain: duration and modulation of expression Hum Gene Ther 1999 10: 201 201
Ohta M. et al. Apomorphine up-regulates NGF and GDNF synthesis in cultured mouse astrocytes Biochem Biophys Res Commun 2000 272: 18 18
Zhou J. et al. Differential expression of mRNAs of GDNF family in the striatum following 6-OHDA-induced lesion Neuroreport 2000 11: 3289 3289
Chamberlin N.L., Du B., de Lacalle S., Saper C.B. . Recombinant adeno-associated virus vector: use for transgene expression and anterograde tract tracing in the CNS Brain Res 1998 793: 169 169
Connor B. et al. Glial cell line-derived neurotrophic factor (GDNF) gene delivery protects dopaminergic terminals from degeneration Exp Neurol 2001 169: 83 83
Kirik D., Georgievska B., Rosenblad C., Bjorklund A. . Delayed infusion of GDNF promotes recovery of motor function in the partial lesion model of Parkinson's disease Eur J Neurosci 2001 13: 1589 1589
Akerud P. et al. Differential effects of glial cell line-derived neurotrophic factor and neurturin on developing and adult substantia nigra dopaminergic neurons J Neurochem 1999 73: 70 70
Horger B.A. et al. Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons J Neurosci 1998 18: 4929 4929
Rosenblad C. et al. In vivo protection of nigral dopamine neurons by lentiviral gene transfer of the novel GDNF-family member neublastin/artemin Mol Cell Neurosci 2000 15: 199 199
Fan D. et al. Prevention of dopaminergic neuron death by adeno-associated virus vector-mediated GDNF gene transfer in rat mesencephalic cells in vitro Neurosci Lett 1998 248: 61 61
Matsushita N. et al. Cloning and structural organization of the gene encoding the mouse glial cell line-derived neurotrophic factor, GDNF Gene 1997 203: 149 149
Matsushita T. et al. Adeno-associated virus vectors can be efficiently produced without helper virus Gene Therapy 1998 5: 938 938
Sawada H. et al. Neuroprotective mechanism of glial cell line-derived neurotrophic factor in mesencephalic neurons J Neurochem 2000 74: 1175 1175
Acknowledgements
We thank Masashi Urabe and Dongsheng Fan for helpful advice. We also thank Avigen for providing the AAV vector production system. This study was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas and Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government; by Health Sciences Research Grants from the Ministry of Health Labour and Welfare of Japan; and by Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Corporation (JST).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wang, L., Muramatsu, S., Lu, Y. et al. Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease. Gene Ther 9, 381–389 (2002). https://doi.org/10.1038/sj.gt.3301682
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3301682
Keywords
This article is cited by
-
Long-term benefits of hematopoietic stem cell-based macrophage/microglia delivery of GDNF to the CNS in a mouse model of Parkinson’s disease
Gene Therapy (2024)
-
Focused ultrasound enhanced intranasal delivery of brain derived neurotrophic factor produces neurorestorative effects in a Parkinson’s disease mouse model
Scientific Reports (2019)
-
GDNF-expressing macrophages mitigate loss of dopamine neurons and improve Parkinsonian symptoms in MitoPark mice
Scientific Reports (2018)
-
Neurotensin-polyplex-mediated brain-derived neurotrophic factor gene delivery into nigral dopamine neurons prevents nigrostriatal degeneration in a rat model of early Parkinson’s disease
Journal of Biomedical Science (2015)
-
Neuroprotective potential of pleiotrophin overexpression in the striatonigral pathway compared with overexpression in both the striatonigral and nigrostriatal pathways
Gene Therapy (2014)