Retrograde axonal transport of glial cell line-derived neurotrophic factor in the adult nigrostriatal system suggests a trophic role in the adult.

Tomac, Andreas C.; Widenfalk, Johan; Lin, Leu‐Fen H.; Kohno, Tadahiko; Ebendal, Ted; Hoffer, Barry J.; Olson, Lar̀s

doi:10.1073/pnas.92.18.8274

Cited by 237 publications

(171 citation statements)

References 29 publications

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“…The receptor for GDNF, GDNF receptor ␣1 (GFR␣1), and its signaling tyrosine kinase, Ret, are both highly expressed in SNpc during development (Widenfalk et al, 1997;Yu et al, 1998). As expected for a target-derived factor, GDNF can be specifically transported retrograde from striatum to SNpc (Tomac et al, 1995b). We showed that GDNF uniquely suppressed apoptosis specifically within DA neurons in a primary postnatal culture model established during the first phase of natural cell death (Burke et al, 1998).…”

Section: Discussionmentioning

confidence: 93%

Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

Kholodilov¹,

Yarygina²,

Oo³

et al. 2004

J. Neurosci.

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Glial cell line-derived neurotrophic factor (GDNF) has been shown to protect and restore dopamine (DA) neurons in injury models and is being evaluated for the treatment of Parkinson's disease. Nevertheless, little is known of its physiological role. We have shown that GDNF suppresses apoptosis in DA neurons of the substantia nigra (SN) postnatally both in vitro and during their first phase of natural cell death in vivo. Furthermore, intrastriatal injection of neutralizing antibodies augments cell death, suggesting that endogenous GDNF plays a role as a target-derived factor. Such a role would predict that overexpression of GDNF in striatum would increase the surviving number of SN DA neurons. To test this hypothesis, we used the tetracycline-dependent transcription activator (tTA)/tTA-responsive promoter system to create mice that overexpress GDNF selectively in the striatum, cortex, and hippocampus. These mice demonstrate an increased number of SN DA neurons after the first phase of natural cell death. However, this increase does not persist into adulthood. As adults, these mice also do not have increased dopaminergic innervation of the striatum. They do, however, demonstrate increased numbers of ventral tegmental area (VTA) neurons and increased innervation of the cortex. This morphologic phenotype is associated with an increased locomotor response to amphetamine. We conclude that striatal GDNF is necessary and sufficient to regulate the number of SN DA neurons surviving the first phase of natural cell death, but it is not sufficient to increase their final adult number. GDNF in VTA targets, however, is sufficient to regulate the adult number of DA neurons.

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Section: Discussionmentioning

confidence: 93%

Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

Kholodilov¹,

Yarygina²,

Oo³

et al. 2004

J. Neurosci.

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“…This DA cell protection in the SN may be owing to the GDNF produced and released in the striatum (B1300 pg/ striatum corresponding to B0.06 ng/mg of tissue), which is then retrogradely transported to the SN where it initially enhances the resistance of DA neurons to the 6-OHDA lesion. The retrograde transport of GDNF from the striatum to the SN has been demonstrated by Tomac et al 31 The effect of GDNF may also result from the retrograde transport of the vector itself from the striatum to the SN where it can produce neurotrophic factor. The retrograde transport of Ad vectors from the striatum to the SN has been reported by Byrnes et al 32 In our study, the levels of GDNF measured in the striatum were sufficient to protect DA neurons from the 6-OHDA lesion although they were lower than levels observed in other studies.…”

Section: Discussionmentioning

confidence: 99%

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

Thi¹,

Saillour²,

Ferrero³

et al. 2006

Gene Ther

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The transfer of the Glial cell line-derived neurotrophic factor (GDNF) gene to the central nervous system by a recombinant adenoviral vector (Ad) was studied. We constructed the adenovirus vector Ad-NSE-GDNF from which the E1, E3/E4 regions of Ad5 have been deleted and in which the GDNF gene was under the control of a neuron-specific enolase (NSE) promoter. The vector was injected into the striatum of a rat model of Parkinson's disease. We found that (i) the NSE promoter can restrict transgene expression in neurons; (ii) Ad-NSE-GDNF significantly protected dopaminergic (DA) neurons in the substantia nigra (SN) but did not reverse the impairments of amphetamine-induced rotational behavior in lesioned rats.

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“…This was possibly because of retrograde delivery from striatal dopaminergic nerve terminals to the cell bodies in the SNpc (Tomac et al, 1995) and anterograde axonal transport from striatal neurons to the afferent regions via the indirect pathway, plus axonal sprouting between the two striatal hemispheres (Ciesielska et al, 2011;Richardson et al, 2011). These off-target effects may provide some advantages in GDNF application for PD treatment, but levels of GDNF transported indirectly to these afferent regions are unpredictable, particularly when higher vector doses or longer expression times are required (Bartus et al, 2011;Drinkut et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Transgenic Expression of Human Glial Cell Line-Derived Neurotrophic Factor from Integration-Deficient Lentiviral Vectors is Neuroprotective in a Rodent Model of Parkinson's Disease

et al. 2014

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Standard integration-proficient lentiviral vectors (IPLVs) are effective at much lower doses than other vector systems and have shown promise for gene therapy of Parkinson's disease (PD). Their main drawback is the risk of insertional mutagenesis. The novel biosafety-enhanced integration-deficient lentiviral vectors (IDLVs) may offer a significant enhancement in biosafety, but have not been previously tested in a model of a major disease. We have assessed biosafety and transduction efficiency of IDLVs in a rat model of PD, using IPLVs as a reference. Genomic insertion of lentivectors injected into the lesioned striatum was studied by linear amplification-mediated polymerase chain reaction (PCR), followed by deep sequencing and insertion site analysis, demonstrating lack of significant IDLV integration. Reporter gene expression studies showed efficient, long-lived, and transcriptionally targeted expression from IDLVs injected ahead of lesioning in the rat striatum, although at somewhat lower expression levels than from IPLVs. Transgenic human glial cell line-derived neurotrophic factor (hGDNF) expression from IDLVs was used for a long-term investigation of lentivectormediated, transcriptionally targeted neuroprotection in this PD rat model. Vectors were injected before striatal lesioning, and the results showed improvements in nigral dopaminergic neuron survival and behavioral tests regardless of lentiviral integration proficiency, although they confirmed lower expression levels of hGDNF from IDLVs. These data demonstrate the effectiveness of IDLVs in a model of a major disease and indicate that these vectors could provide long-term PD treatment at low dose, combining efficacy and biosafety for targeted central nervous system applications.

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Retrograde axonal transport of glial cell line-derived neurotrophic factor in the adult nigrostriatal system suggests a trophic role in the adult.

Abstract: The recently cloned, distant member of the transforming growth factor 13

Cited by 237 publications

References 29 publications

Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

Regulation of the Development of Mesencephalic Dopaminergic Systems by the Selective Expression of Glial Cell Line-Derived Neurotrophic Factor in Their Targets

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

Transgenic Expression of Human Glial Cell Line-Derived Neurotrophic Factor from Integration-Deficient Lentiviral Vectors is Neuroprotective in a Rodent Model of Parkinson's Disease

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