Research ArticleParkinson’s Disease

α-Synuclein–Induced Down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons

Science Translational Medicine  05 Dec 2012:
Vol. 4, Issue 163, pp. 163ra156
DOI: 10.1126/scitranslmed.3004676

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NURRishing Dopamine Neurons with GDNF

Glial cell line–derived neurotrophic factor (GDNF) and its close relative neurturin are currently in clinical trials for neuroprotection in patients with Parkinson disease (PD). Although effective in classic neurotoxin animal models of this disease, GDNF has failed to afford protection in PD rodent models in which dopamine neurons are killed by α-synuclein toxicity. Using a rat model of α-synuclein–mediated PD, Decressac et al. now show that excess cellular concentrations of α-synuclein effectively block the trophic response of dopamine neurons to GDNF. They provide evidence that blockade of GDNF signaling is caused by reduced expression of the transcription factor Nurr1 and its downstream target, the GDNF receptor Ret. Deletion of Nurr1 resulted in reduced Ret expression, accompanied by a complete failure of dopamine neurons to respond to exogenously applied GDNF. However, when the investigators induced expression of Nurr1, Ret receptor expression was restored as well as the response to GDNF in the dopamine neurons subjected to α-synuclein toxicity. These results suggest that Nurr1 is a key player in the cellular defense against α-synuclein toxicity and highlight Nurr1 as a promising new target for neuroprotective therapy.

Abstract

Glial cell line–derived neurotrophic factor (GDNF) and its close relative neurturin are currently in clinical trials for neuroprotection in patients with Parkinson disease (PD). However, in animal models of PD, GDNF fails to protect nigral dopamine (DA) neurons against α-synuclein–induced neurodegeneration. Using viral vector delivery of human wild-type α-synuclein to nigral DA neurons in rats, we show that the intracellular response to GDNF is blocked in DA neurons that overexpress α-synuclein. This block is accompanied by reduced expression of the transcription factor Nurr1 and its downstream target, the GDNF receptor Ret. We found that Ret expression was also reduced in nigral DA neurons in PD patients. Conditional knockout of Nurr1 in mice resulted in reduced Ret expression and blockade of the response to GDNF, whereas overexpression of Nurr1 restored signaling, providing protection of nigral DA neurons against α-synuclein toxicity. These results suggest that Nurr1 is a regulator of neurotrophic factor signaling and a key player in the cellular defense against α-synuclein toxicity.

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