TY - JOUR
T1 - Glial cell line-derived neurotrophic factor (GDNF) gene delivery protects dopaminergic terminals from degeneration
AU - Connor, Bronwen
AU - Kozlowski, Dorothy A.
AU - Unnerstall, James R.
AU - Elsworth, John D.
AU - Tillerson, Jennifer L.
AU - Schallert, Timothy
AU - Bohn, Martha C.
N1 - Funding Information:
This work was supported by NIH Grants NS31957, NS39267, and MH57958, and the Medical Research Institute Council of Children’s Memorial Hospital. The AdGDNF vector was a generous gift of Genetic Therapy Inc/Novartis. The authors thank Dr. Beverly Da-vidson and Mr. Richard Anderson at the University of Iowa Gene Transfer Vector Core for preparation of vector stocks and thank Chung M. Huang and Sol A. Lee for their assistance in carrying out the in situ hybridization assays. The University of Iowa Vector Core is supported by NIH and the Carver Foundation. B.C. is a recipient of a New Zealand Neurological Foundation Post-Doctoral Fellowship.
PY - 2001
Y1 - 2001
N2 - Previously, we observed that injection of an adenoviral (Ad) vector expressing glial cell line-derived neurotrophic factor (GDNF) into the striatum, but not the substantia nigra (SN), prior to a partial 6-OHDA lesion protects dopaminergic (DA) neuronal function and prevents the development of behavioral impairment in the aged rat. This suggests that striatal injection of AdGDNF maintains nigrostriatal function either by protecting DA terminals or by stimulating axonal sprouting to the denervated striatum. To distinguish between these possible mechanisms, the present study examines the effect of GDNF gene delivery on molecular markers of DA terminals and neuronal sprouting in the aged (20 month) rat brain. AdGDNF or a control vector coding for β-galactosidase (AdLacZ) was injected unilaterally into either the striatum or the SN. One week later, rats received a unilateral intrastriatal injection of 6-OHDA on the side of vector injection. Two weeks postlesion, rats injected with AdGDNF into either the striatum or the SN exhibited a reduction in the area of striatal denervation and increased binding of the DA transporter ligand [125I]IPCIT in the lesioned striatum compared to control animals. Furthermore, injections of AdGDNF into the striatum, but not the SN, increased levels of tyrosine hydroxylase mRNA in lesioned DA neurons in the SN and prevented the development of amphetamine-induced rotational asymmetry. In contrast, the level of T1 α-tubulin mRNA, a marker of neuronal sprouting, was not increased in lesioned DA neurons in the SN following injection of AdGDNF either into the striatum or into the SN. These results suggest that GDNF gene delivery prior to a partial lesion ameliorates damage caused by 6-OHDA in aged rats by inhibiting the degeneration of DA terminals rather than by inducing sprouting of nigrostriatal axons.
AB - Previously, we observed that injection of an adenoviral (Ad) vector expressing glial cell line-derived neurotrophic factor (GDNF) into the striatum, but not the substantia nigra (SN), prior to a partial 6-OHDA lesion protects dopaminergic (DA) neuronal function and prevents the development of behavioral impairment in the aged rat. This suggests that striatal injection of AdGDNF maintains nigrostriatal function either by protecting DA terminals or by stimulating axonal sprouting to the denervated striatum. To distinguish between these possible mechanisms, the present study examines the effect of GDNF gene delivery on molecular markers of DA terminals and neuronal sprouting in the aged (20 month) rat brain. AdGDNF or a control vector coding for β-galactosidase (AdLacZ) was injected unilaterally into either the striatum or the SN. One week later, rats received a unilateral intrastriatal injection of 6-OHDA on the side of vector injection. Two weeks postlesion, rats injected with AdGDNF into either the striatum or the SN exhibited a reduction in the area of striatal denervation and increased binding of the DA transporter ligand [125I]IPCIT in the lesioned striatum compared to control animals. Furthermore, injections of AdGDNF into the striatum, but not the SN, increased levels of tyrosine hydroxylase mRNA in lesioned DA neurons in the SN and prevented the development of amphetamine-induced rotational asymmetry. In contrast, the level of T1 α-tubulin mRNA, a marker of neuronal sprouting, was not increased in lesioned DA neurons in the SN following injection of AdGDNF either into the striatum or into the SN. These results suggest that GDNF gene delivery prior to a partial lesion ameliorates damage caused by 6-OHDA in aged rats by inhibiting the degeneration of DA terminals rather than by inducing sprouting of nigrostriatal axons.
KW - Adenoviral vector
KW - Aging
KW - Axonal sprouting
KW - Dopamine transporter
KW - Gene therapy
KW - Parkinson's disease
KW - Phenotypic expression
KW - Tyrosine hydroxylase
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U2 - 10.1006/exnr.2001.7638
DO - 10.1006/exnr.2001.7638
M3 - Article
C2 - 11312561
AN - SCOPUS:0035004246
SN - 0014-4886
VL - 169
SP - 83
EP - 95
JO - Neurodegeneration
JF - Neurodegeneration
IS - 1
ER -