Glial cell line-derived neurotrophic factor in the substantia nigra from control and parkinsonian brains

Mogi, Makio; Togari, Akifumi; Kondo, Tomoyoshi; Mizuno, Yoshikuni; Kogure, Osamu; Kuno, Sadako; Ichinose, Hiroshi; Nagatsu, Toshiharu

doi:10.1016/s0304-3940(01)01577-4

Cited by 46 publications

(34 citation statements)

References 17 publications

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“…Post-mortem studies investigating GDNF distribution in the human parkinsonian brain have yielded conflicting results. In situ hybridization studies failed to detect GDNF mRNA in the human midbrain (Hunot et al, 1996), and no significant differences were found in GDNF content in the caudate-putamen and substantia nigra between PD and control samples (Mogi et al, 2001). Since the levels of other growth factors are decreased in PD brains, it was suggested that the unchanged levels of GDNF in PD might be due to compensatory production by glial cells (Mogi et al, 2001).…”

Section: Gdnf Expression Upon Nigrostriatal Injury: Role Of Neuronglimentioning

confidence: 99%

“…In situ hybridization studies failed to detect GDNF mRNA in the human midbrain (Hunot et al, 1996), and no significant differences were found in GDNF content in the caudate-putamen and substantia nigra between PD and control samples (Mogi et al, 2001). Since the levels of other growth factors are decreased in PD brains, it was suggested that the unchanged levels of GDNF in PD might be due to compensatory production by glial cells (Mogi et al, 2001). However, using immunohistochemistry, large reductions in GDNF content are reported in surviving PD substantia nigra neurons (Chauhan et al, 2001).…”

Section: Gdnf Expression Upon Nigrostriatal Injury: Role Of Neuronglimentioning

confidence: 99%

“…Concerning glial cell line-derived neurotrophic factor (GDNF), postmortem studies investigating its distribution in the human parkinsonian brain have yielded conflicting results (Hunot et al, 1996;Chauhan et al, 2001;Mogi et al, 2001). Since GDNF expression is reduced in the adult brain, the use of techniques that enhance the detection of low copy mRNA transcripts may be crucial for accurate quantification of its expression.…”

Section: Introduction: the Relevance Of Studying The Endogenous Gdnf mentioning

confidence: 99%

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Driving GDNF expression: The green and the red traffic lights

Saavedra

Baltazar

Duarte

2008

Progress in Neurobiology

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Section: Gdnf Expression Upon Nigrostriatal Injury: Role Of Neuronglimentioning

confidence: 99%

Section: Gdnf Expression Upon Nigrostriatal Injury: Role Of Neuronglimentioning

confidence: 99%

Section: Introduction: the Relevance Of Studying The Endogenous Gdnf mentioning

confidence: 99%

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Driving GDNF expression: The green and the red traffic lights

Saavedra

Baltazar

Duarte

2008

Progress in Neurobiology

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“…Such an approach may therefore lead to maximal transgene expression in the required brain region, while preventing offtarget effects resulting from ectopic expression in afferent regions. Moreover, since astrocytes are the major source of GDNF upon brain injury and may be responsible for maintenance of GDNF levels in the SN of PD brains (Mogi et al, 2001;Saavedra et al, 2008), astrocytic-hGDNF expression by the lentiviral vector GFAPp would be beneficial as demonstrated in this study.…”

Section: Discussionmentioning

confidence: 89%

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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“…30 GDNF levels in various parts of the brain are reported to be no different in parkinsonian than in control patient brains. 31 GDNF mRNA expression was increased in the putamen of PD patients, however, compared with controls, 32 and so there is no evidence that loss of GDNF is responsible for development of PD.…”

Section: Gdnfmentioning

confidence: 92%

Treatment of Parkinson’s Disease with Trophic Factors

2008

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Summary: Trophic factors are proteins that support and protect subpopulations of cells. A number have been reported to act on dopaminergic neurons in vitro and in vivo, making them potential therapeutic candidates for Parkinson's disease. All of these candidate factors protect dopaminergic neurons if given prior to, or with, selective neurotoxins. Fewer trophic factors, primarily glial-derived neurotrophic factor (GDNF) and its relative, neurturin (NRTN; also known as NTN), have been shown to restore function in damaged dopamine neurons after the acute effects of neurotoxins have subsided. A major barrier to clinical translation has been delivery. GDNF delivered by intracerebroventricular injection in patients was ineffective, probably because GDNF did not reach the target, the putamen, and intraputaminal infusion was ineffective, probably because of limited distribution within the putamen. A randomized clinical trial with gene therapy for NRTN is underway, in an attempt to overcome these problems with targeting and distribution. Other strategies are available to induce trophic effects in the CNS, but have not yet been the focus of human research. To date, clinical trials have focused on restoration of function (i.e., improvement of parkinsonism). Protection (i.e., slowing or halting disease progression and functional decline) might be a more robust effect of trophic agents. Laboratory research points to their effectiveness in protecting neurons and even restoring dopaminergic function after a monophasic neurotoxic insult. Utility for such compounds in patients with Parkinson's disease and ongoing loss of dopaminergic neurons remains to be proven.

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Glial cell line-derived neurotrophic factor in the substantia nigra from control and parkinsonian brains

Cited by 46 publications

References 17 publications

Driving GDNF expression: The green and the red traffic lights

Driving GDNF expression: The green and the red traffic lights

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

Treatment of Parkinson’s Disease with Trophic Factors

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