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

Decressac, Mickael LU ; Kadkhodaei, Banafsheh; Mattsson, Bengt LU ; Laguna, Ariadna; Perlmann, Thomas and Björklund, Anders LU (2012) In Science Translational Medicine 4(163). p.156-163
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Translational Medicine
volume
4
issue
163
pages
156 - 163
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • wos:000311996700003
  • pmid:23220632
  • scopus:84870687953
ISSN
1946-6242
DOI
10.1126/scitranslmed.3004676
language
English
LU publication?
yes
id
a5bc0156-97ee-463b-8f9f-a4521a35ffd7 (old id 3347479)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23220632?dopt=Abstract
date added to LUP
2013-01-02 15:19:58
date last changed
2017-11-19 03:07:33
@article{a5bc0156-97ee-463b-8f9f-a4521a35ffd7,
  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.},
  author       = {Decressac, Mickael and Kadkhodaei, Banafsheh and Mattsson, Bengt and Laguna, Ariadna and Perlmann, Thomas and Björklund, Anders},
  issn         = {1946-6242},
  language     = {eng},
  number       = {163},
  pages        = {156--163},
  publisher    = {American Association for the Advancement of Science (AAAS)},
  series       = {Science Translational Medicine},
  title        = {α-Synuclein-Induced Down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons.},
  url          = {http://dx.doi.org/10.1126/scitranslmed.3004676},
  volume       = {4},
  year         = {2012},
}