| 1. |
- Decressac, Mickael, et al.
(författare)
-
α-Synuclein-Induced Down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons.
- 2012
-
Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 4:163, s. 156-163
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 2. |
- Kadkhodaei, Banafsheh, et al.
(författare)
-
Nurr1 Is Required for Maintenance of Maturing and Adult Midbrain Dopamine Neurons
- 2009
-
Ingår i: The Journal of Neuroscience. - 1529-2401. ; 29:50, s. 15923-15932
-
Tidskriftsartikel (refereegranskat)abstract
- Transcription factors involved in the specification and differentiation of neurons often continue to be expressed in the adult brain, but remarkably little is known about their late functions. Nurr1, one such transcription factor, is essential for early differentiation of midbrain dopamine (mDA) neurons but continues to be expressed into adulthood. In Parkinson's disease, Nurr1 expression is diminished and mutations in the Nurr1 gene have been identified in rare cases of disease; however, the significance of these observations remains unclear. Here, a mouse strain for conditional targeting of the Nurr1 gene was generated, and Nurr1 was ablated either at late stages of mDA neuron development by crossing with mice carrying Cre under control of the dopamine transporter locus or in the adult brain by transduction of adeno-associated virus Cre-encoding vectors. Nurr1 deficiency in maturing mDA neurons resulted in rapid loss of striatal DA, loss of mDA neuron markers, and neuron degeneration. In contrast, a more slowly progressing loss of striatal DA and mDA neuron markers was observed after ablation in the adult brain. As in Parkinson's disease, neurons of the substantia nigra compacta were more vulnerable than cells in the ventral tegmental area when Nurr1 was ablated at late embryogenesis. The results show that developmental pathways play key roles for the maintenance of terminally differentiated neurons and suggest that disrupted function of Nurr1 and other developmental transcription factors may contribute to neurodegenerative disease.
|
|
| 3. |
- Kadkhodaei, Banafsheh
(författare)
-
Transcription factor control in neuronal maintenance and survival
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Transcription factor (TF) Nurr1 is essential for the development of a group of dopamine neurons that are located in the ventral midbrain (also referred to as mesencephalon). A progressive pathology of these midbrain dopamine (mDA) neurons is evident in Parkinson s disease, the most frequent neurodegenerative movement disorder. In addition Nurr1 is expressed in a number of other CNS areas. In the hippocampus, Nurr1 is co-expressed with its homologues Nur77 and Nor1, collectively named for NR4A TF s. These TF s are rapidly and strongly induced in response to stressful stimuli and an acute NR4A induction has been noted in e. g. hippocampal, cortical and striatal neurons after ischemia, seizures and focal brain injury in rodents. However, the functional roles of the stress-induced NR4A-expression have remained unknown. As Nurr1 is critical for the mDA neuron development and is widely expressed in the adult CNS, we hypothesized that Nurr1 might also play a crucial role in maintaining mature neurons. To address this hypothesis, the functional consequences of gain-of-function or loss-of-function of NR4A proteins were assessed in maturing and adult neurons in vitro and in vivo. The research presented in paper I & II describes the consequences of spatiotemporal ablation of Nurr1 in mDA neurons in mice. Our results revealed that Nurr1 continues to be critical for the maturing mDA neurons and for maintaining a DA phenotype in the mDA neurons of adult mice. In paper III, the function of stress-induced NR4A proteins was characterized in vitro in cultured neurons and in vivo in the hippocampi of mice. The data revealed that stress-induced NR4A promoted neuroprotection in neurons, presumably by up-regulating a subset of neuroprotective genes. The work in paper IV deals with the mechanism by which Nurr1 mediates transcriptional activation. We identified a novel putative Nurr1 coregulator-binding site that might recruit as yet unknown coregulators.
|
|
| 4. |
- Kadkhodaei, Banafsheh, et al.
(författare)
-
Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons
- 2013
-
Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:6, s. 2360-2365
-
Tidskriftsartikel (refereegranskat)abstract
- Developmental transcription factors important in early neuron specification and differentiation often remain expressed in the adult brain. However, how these transcription factors function to mantain appropriate neuronal identities in adult neurons and how transcription factor dysregulation may contribute to disease remain largely unknown. The transcription factor Nurr1 has been associated with Parkinson's disease and is essential for the development of ventral midbrain dopamine (DA) neurons. We used conditional Nurr1 gene-targeted mice in which Nurr1 is ablated selectively in mature DA neurons by treatment with tamoxifen. We show that Nurr1 ablation results in a progressive pathology associated with reduced striatal DA, impaired motor behaviors, and dystrophic axons and dendrites. We used laser-microdissected DA neurons for RNA extraction and next-generation mRNA sequencing to identify Nurr1-regulated genes. This analysis revealed that Nurr1 functions mainly in transcriptional activation to regulate a battery of genes expressed in DA neurons. Importantly, nuclear-encoded mitochondrial genes were identified as the major functional category of Nurr1-regulated target genes. These studies indicate that Nurr1 has a key function in sustaining high respiratory function in these cells, and that Nurr1 ablation in mice recapitulates early features of Parkinson's disease.
|
|
| 5. |
- Malewicz, Michal, et al.
(författare)
-
Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair
- 2011
-
Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 25:19, s. 2031-2040
-
Tidskriftsartikel (refereegranskat)abstract
- DNA-dependent protein kinase (DNA-PK) is a central regulator of DNA double-strand break (DSB) repair; however, the identity of relevant DNA-PK substrates has remained elusive. NR4A nuclear orphan receptors function as sequence-specific DNA-binding transcription factors that participate in adaptive and stress-related cell responses. We show here that NR4A proteins interact with the DNA-PK catalytic subunit and, upon exposure to DNA damage, translocate to DSB foci by a mechanism requiring the activity of poly(ADP-ribose) polymerase-1 (PARP-1). At DNA repair foci, NR4A is phosphorylated by DNA-PK and promotes DSB repair. Notably, NR4A transcriptional activity is entirely dispensable in this function, and core components of the DNA repair machinery are not transcriptionally regulated by NR4A. Instead, NR4A functions directly at DNA repair sites by a process that requires phosphorylation by DNA-PK. Furthermore, a severe combined immunodeficiency (SCID)-causing mutation in the human gene encoding the DNA-PK catalytic subunit impairs the interaction and phosphorylation of NR4A at DSBs. Thus, NR4As represent an entirely novel component of DNA damage response and are substrates of DNA-PK in the process of DSB repair.
|
|
