ALPHA-SynucIein-Induced Down-Regulation of Nurri Disrupts GDNF Signaling in Nigral Dopamine Neurons,

摘要

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 a-synuclein-induced neurodegeneration. Using viral vector delivery of human wild-type a-synuclein to nigral DA neurons in rats, we show that the intracellular response to GDNF is blocked in DA neurons that overexpress a-synuclein. This block is accompanied by reduced expression of the transcription factor Nurri 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 Nurri in mice resulted in reduced Ret expression and blockade of the response to GDNF, whereas overexpression of Nurri restored signaling, providing protection of nigral DA neurons against a-synuclein toxicity. These results suggest that Nurri is a regulator of neurotrophic factor signaling and a key player in the cellular defense against a-synuclein toxicity.