α-Synuclein-Induced Down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons.
Författare
Summary, in English
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.
Publiceringsår
2012
Språk
Engelska
Sidor
156-163
Publikation/Tidskrift/Serie
Science Translational Medicine
Volym
4
Issue
163
Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
American Association for the Advancement of Science (AAAS)
Ämne
- Neurosciences
Status
Published
Forskningsgrupp
- Neurobiology
ISBN/ISSN/Övrigt
- ISSN: 1946-6242