Does neuronal expression of GDNF effectively protect dopaminergic neurons in a rat model of Parkinson's disease?

Thi, Ngo; Saillour, P; Ferrero, Lucy; Paunio, Tiina; Mallet, Jacques

doi:10.1038/sj.gt.3302844

Cited by 15 publications

(8 citation statements)

References 44 publications

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“…First, neurotrophin gene therapy, and in particular GDNF gene therapy, is known to rescue the nigra-striatal system in experimental PD when the GDNF gene is injected directly into the brain (6)(7)(8)(9)(10). The present study extends these findings to the experimental setting where the GDNF transgene is administered intravenously without viral vectors.…”

Section: Discussionsupporting

confidence: 70%

“…However, GDNF does not cross the blood-brain barrier (BBB) (4,5). The intra-cerebral injection of either adeno-associated virus (AAV) or retroviral vectors expressing GDNF rescues neurons of the nigrastriatal tract in experimental PD (6)(7)(8)(9)(10). Since viral vectors do not cross the BBB, viral GDNF gene therapy of PD requires a trans-cranial injection of the virus.…”

Section: Introductionmentioning

confidence: 99%

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Near Complete Rescue of Experimental Parkinson’s Disease with Intravenous, Non-viral GDNF Gene Therapy

Zhang¹,

Pardridge²

2008

Pharm Res

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Purpose. Rats with experimental Parkinson's disease (PD) are treated with intravenous glial-derived neurotrophic factor (GDNF) plasmid DNA and non-viral gene therapy using Trojan horse liposomes (THLs) targeted with a monoclonal antibody (MAb) to the rat transferrin receptor (TfR). The GDNF transgene expression is under the influence of the rat tyrosine hydroxylase (TH) promoter. Methods. The GDNF expression plasmid is designated pTHproGDNF. Rats were treated with 3 weekly injections of THLs starting 1 week after the intra-cerebral injection of 6-hydroxydopamine. The dose of the pTHproGDNF was 10 μg/rat/weekly injection. Rats were tested with three assays of neurobehavior, and terminal striatal TH enzyme activity was measured at 6 weeks following toxin administration, which is 3 weeks following the last administration of THLs. Results. Apomorphine-induced contralateral rotation was reduced 87% by THL gene therapy; amphetamine-induced ipsilateral rotation was reduced 90% by THL gene therapy; whisker-induced forelimb placement abnormalities were reduced 77% with THL gene therapy. The improvement in neurobehavior correlated with a lasting 77% increase in striatal TH enzyme activity, relative to saline treated rats. Conclusions. Near complete abrogation of the neurotoxin effects are achieved with multiple intravenous dosing of GDNF plasmid DNA gene therapy, using receptor-targeted THLs, and a region-specific promoter.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Near Complete Rescue of Experimental Parkinson’s Disease with Intravenous, Non-viral GDNF Gene Therapy

Zhang¹,

Pardridge²

2008

Pharm Res

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“…In the case of PD, the family of ligands related to GDNF has received the most attention, but the most prominent receptor (RET) for these ligands is not required for the maintenance of adult neurons (Jain et al 2006). GDNF is normally synthesized by astrocytes, and recent studies developing a GDNF-based gene therapy suggests that expression in astrocytes has a better effect on dopamine neurons than expression in neurons (Do Thi et al 2007). These results suggest that the neuroprotective responses of GDNF are indirect.…”

Section: Discussionmentioning

confidence: 99%

Signaling Pathways Controlling Neural Stem Cells Slow Progressive Brain Disease

Androutsellis-Theotokis¹,

Rueger²,

Mkhikian³

et al. 2008

Cold Spring Harbor Symposia on Quantitative Biology

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The identification and characterization of multipotent neural precursors open the possibility of transplant therapies, but this approach is complicated by the widespread pathology of many degenerative diseases. Activation of endogenous precursors that support regenerative mechanisms is a possible alternative. We have previously shown that Notch ligands promote stem cell survival in vitro. Here, we show that there is an intimate interaction between insulin and Notch receptor signaling. Notch ligands also expand stem cell numbers in vivo with correlated benefits in brain ischemia. We now show that insulin promotes recovery of injured dopamine neurons in the adult brain. This response suggests that activating survival mechanisms in neural stem cells will promote recovery from progressive degenerative disease.

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“…This cDNA was then subcloned into a bicistronic vector containing enhanced green fluorescent protein (EGFP) behind an internal ribosomal entry site (IRES). The noggin sequence was verified and the noggin-IRES-EGFP construct was further subcloned into a pNSE-Ex4 plasmid (Do Thi et al, 2007), which contains 4 kb of rat NSE gene DNA with 2.8 kb of 5' flanking DNA, 50 bp of the non-translated exon I, 1.2 kb of intron I and 6 bp of exon II (with no AUG). The noggin-IRES-EGFP fragment was inserted downstream of the NSE promoter and upstream of an SV40 polyadenylation signal, at the Sal I site of the pNSE-Ex4 plasmid.…”

Section: Methodsmentioning

confidence: 99%

Bone morphogenetic protein regulation of enteric neuronal phenotypic diversity: Relationship to timing of cell cycle exit

Chalazonitis

Pham

et al. 2008

J of Comparative Neurology

110

151

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The effects of bone morphogenetic protein (BMP) signaling on enteric neuron development were examined in transgenic mice over expressing either the BMP inhibitor, noggin, or BMP4 under control of the neuron specific enolase (NSE) promoter. Noggin antagonism of BMP signaling increased total numbers of enteric neurons and those of subpopulations derived from precursors that exit the cell cycle early in neurogenesis (serotonin, calretinin, calbindin). In contrast, noggin overexpression decreased numbers of neurons derived from precursors that exit the cell cycle late (γ-aminobutyric acid, tyrosine hydroxylase [TH], dopamine transporter, calcitonin gene related peptide, TrkC). Numbers of TH-and TrkC-expressing neurons were increased by overexpression of BMP4. These observations are consistent with the idea that phenotypic expression in the enteric nervous system (ENS) is determined, in part, by the number of proliferative divisions neuronal precursors undergo before their terminal mitosis. BMP signaling may thus regulate enteric neuronal phenotypic diversity by promoting the exit of precursors from the cell cycle. BMP2 increased the numbers of TH-and TrkC-expressing neurons developing in vitro from immunoselected enteric crest-derived precursors; BMP signaling may thus also specify or promote the development of dopaminergic TrkC/NT-3-dependent neurons. The developmental defects in the ENS of noggin overexpressing mice caused a relatively mild disturbance of motility (irregular rapid transit and increased stool frequency, weight, and water content). Although the function of the gut thus displays a remarkable tolerance for ENS defects, subtle functional abnormalities in motility or secretion may arise when ENS defects short of aganglionosis occur during development.

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Does neuronal expression of GDNF effectively protect dopaminergic neurons in a rat model of Parkinson's disease?

Cited by 15 publications

References 44 publications

Near Complete Rescue of Experimental Parkinson’s Disease with Intravenous, Non-viral GDNF Gene Therapy

Near Complete Rescue of Experimental Parkinson’s Disease with Intravenous, Non-viral GDNF Gene Therapy

Signaling Pathways Controlling Neural Stem Cells Slow Progressive Brain Disease

Bone morphogenetic protein regulation of enteric neuronal phenotypic diversity: Relationship to timing of cell cycle exit

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