Glial cell line-derived neurotrophic factor (GDNF) gene delivery protects dopaminergic terminals from degeneration.
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 beta-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 [(125)I]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 alpha-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.
Connor
B
B
Department of Pediatrics, Children's Memorial Institute for Education and Research, Northwestern University Medical School, Chicago, Illinois, 60614, USA.
Kozlowski
D A
DA
Unnerstall
J R
JR
Elsworth
J D
JD
Tillerson
J L
JL
Schallert
T
T
Bohn
M C
MC
D000375:Aging; D000818:Animals; D001345:Autoradiography; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage* / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018377:Neurotransmitter Agents / Q000378:metabolism; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000517:prevention & control*; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D012333:RNA, Messenger; C079213:RTI 121; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine; D004298:Dopamine