In Vivo Protection of Nigral Dopamine Neurons by Lentiviral Gene Transfer of the Novel GDNF-Family Member Neublastin/Artemin

 In Vivo Protection of Nigral Dopamine Neurons by Lentiviral Gene Transfer of the Novel GDNF-Family Member Neublastin/Artemin},
  author={Carl Rosenblad and Mette Gr{\o}nborg and Claus Hansen and Nikolaj S. Blom and Morten Meyer and Jens Leander Johansen and Lone Dag{\o} and Deniz Kirik and Umesh A. Patel and Cecilia Lundberg and Didier Trono and Anders Bj{\"o}rklund and Teit Eliot Johansen},
  journal={Molecular and Cellular Neuroscience},
The glial cell line-derived neurotrophic factor (GDNF)-family of neurotrophic factors consisted until recently of three members, GDNF, neurturin, and persephin. We describe here the cloning of a new GDNF-family member, neublastin (NBN), identical to artemin (ART), recently published (Baloh et al., 1998). Addition of NBN/ART to cultures of fetal mesencephalic dopamine (DA) neurons increased the number of surviving tyrosine hydroxylase (TH)-immunoreactive neurons by approximately 70%, similar to… 
Overexpression of Glial Cell Line-Derived Neurotrophic Factor Using a Lentiviral Vector Induces Time- and Dose-Dependent Downregulation of Tyrosine Hydroxylase in the Intact Nigrostriatal Dopamine System
Results indicate that downregulation of TH protein reflects a compensatory effect in response to continuous GDNF stimulation of the DA neurons mediated by a combination of overactivity at the DA synapse and a direct GDNF-induced action on TH gene expression to maintain long-term DA neuron function within the normal range.
Aberrant Sprouting and Downregulation of Tyrosine Hydroxylase in Lesioned Nigrostriatal Dopamine Neurons Induced by Long-Lasting Overexpression of Glial Cell Line Derived Neurotrophic Factor in the Striatum by Lentiviral Gene Transfer
The results of the amphetamine-induced rotation suggested an initial partial protection followed by a complete recovery, whereas the spontaneous motor behaviors remained impaired, which may be explained by this extensive aberrant fiber sprouting in the downstream striatal target nuclei and/or decreased synthesis of dopamine in the striatum.
Glial Cell Line-Derived Neurotrophic Factor (GDNF) Gene Delivery Protects Dopaminergic Terminals from Degeneration
The 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.
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
The results demonstrate that both nigral and striatal transduction provide significant protection of nigral DA neurons against the toxin-induced degeneration, and provide evidence that rAAV is a highly efficient vector system for long-term expression of therapeutic proteins in the nigrostriatal system.
Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease
Significant behavioral recovery was observed from 4–20 weeks following AAV-GDNFflag injection, indicating 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.
Neuroprotection in the rat Parkinson model by intrastriatal GDNF gene transfer using a lentiviral vector
Striatal delivery of rLV-GDNF efficiently protected the nigral dopamine neurons and their projection, against the 6-OHDA lesion (65–77% of intact side).
Long‐term striatal overexpression of GDNF selectively downregulates tyrosine hydroxylase in the intact nigrostriatal dopamine system
These findings indicate that sustained GDNF administration to intact nigrostriatal dopamine neurons selectively reduces tyrosine hydroxylase expression, without altering striatal dopamine transmission to the extent that compensatory changes in several other components related to dopamine storage and signalling occur.


Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo
It is concluded that intracerebral GDNF administration exerts both protective and reparative effects on the nigrostriatal dopamine system, which may have implications for the development of new treatment strategies for Parkinson's disease.
Protection and regeneration of nigral dopaminergic neurons by neurturin or GDNF in a partial lesion model of Parkinson's disease after administration into the striatum or the lateral ventricle
GDNF is highly effective as a neuroprotective and axon growth‐stimulating agent in the IS 6‐OHDA lesion model after both IS and ICV administration, and the lower efficacy of NTN after IS, and particularly ICV, administration may be explained by the poor solubility and diffusion properties at neutral pH.
Differential Effects of Glial Cell Line‐Derived Neurotrophic Factor and Neurturin on Developing and Adult Substantia Nigra Dopaminergic Neurons
Neurturin was found to be as potent as GDNF at preventing the death of nigral dopaminergic neurons, but only GDNF induced tyrosine hydroxylase staining, sprouting, or hypertrophy of dopamine neurons in vivo.
Behavioral and Cellular Protection of Rat Dopaminergic Neurons by an Adenoviral Vector Encoding Glial Cell Line-Derived Neurotrophic Factor
It is demonstrated that Ad GDNF can sustain increased levels of biosynthesized GDNF in the terminal region of DA neurons for at least 7 weeks and that this GDNF slows the degeneration ofDA neurons and prevents the appearance of dopamine dependent motor asymmetries in a rat model of Parkinson's disease (PD).
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.
It is found that mesencephalic nigral dopamine neurons of animals treated with the Ad-GDNF were protected, whereas those of animalstreated with theAd-beta-galactosidase were not, and this protection was associated with a difference in motor function: amphetamine-induced turning was much lower in animals that received the adenovirus encoding GDNF than in the Animals that received Ad-beta -galactOSidase.
Glial cell line‐derived neurotrophic factor prevents death, but not reductions in tyrosine hydroxylase, of injured nigrostriatal neurons in adult rats
  • X. Lu, T. Hagg
  • Biology
    The Journal of comparative neurology
  • 1997
It is shown that GDNF (3 μg per day and higher) can promote the survival of all axotomized nigrostriatal dopaminergic neurons of adult rats when continuously infused for 2 weeks close to the substantia nigra, compared to only ∼30% survival with control infusions.
Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain
It is reported that axotomy resulted in loss of half the tyrosine hydroxylase-expressing neurons in the substantia nigra, which suggests that GDNF or related molecules may be useful for the treatment of Parkinson's disease.
Dopaminergic Neurons Protected from Degeneration by GDNF Gene Therapy
Results suggest that Ad vector-mediated GDNF gene therapy may slow the DA neuronal cell loss in humans with Parkinson's disease.
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.
Data indicate that the use of rAAV, a noncytopathic viral vector, can promote delivery of functional levels of GDNF in a degenerative model of Parkinson's disease.