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Combined Nurr1 and Foxa2 roles in the therapy of Parkinson's disease.

Oh SM, Chang MY, Song JJ, Rhee YH, Joe EH, Lee HS, Yi SH, Lee SH - EMBO Mol Med (2015)

Bottom Line: In addition to their proposed cell-autonomous actions in mDA neurons, forced expression of these factors in neighboring glia synergistically protects degenerating mDA neurons in a paracrine mode.As a consequence of these bimodal actions, adeno-associated virus (AAV)-mediated gene delivery of Nurr1 and Foxa2 in a PD mouse model markedly protected mDA neurons and motor behaviors associated with nigrostriatal DA neurotransmission.The effects of the combined gene delivery were dramatic, highly reproducible, and sustained for at least 1 year, suggesting that expression of these factors is a promising approach in PD therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.

No MeSH data available.


Related in: MedlinePlus

Mechanisms for the paracrine neuroprotective roles by Nurr1- and Foxa2-expressing glial cellsA Real-time PCR analysis for pro-inflammatory cytokines and neurotrophic factors. BV2 microglia and primarily cultured astrocytes were transduced with C, N, F, and NF. Real-time PCR analyses were carried out 12 h after LPS (100 ng/ml, for pro-inflammatory cytokine expressions), IL-4 (10 ng/ml, other M2 markers), or without the treatment (neurotrophic factors). Significantly different from the control (C)*, N#, F‡ at P < 0.05, n = 3–6 PCRs; one-way ANOVA followed by Bonferroni post hoc test.B, C NO levels released (B) and arginase activity (C) were measured in the media and cells for BV-2 microglia cultures, respectively. Significantly different from the control (C)*, N#, F‡ at P < 0.05, n = 3 reactions, P-values: 0.027 (N-CM*), 0.033 (F-CM*), 0.018 (NF-CM*), and 0.033 (NF-CM‡) for the NO level, 0.011*, 0.025#, and 0.036‡ for the arginase activity; one-way ANOVA followed by Bonferroni post hoc test.
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fig04: Mechanisms for the paracrine neuroprotective roles by Nurr1- and Foxa2-expressing glial cellsA Real-time PCR analysis for pro-inflammatory cytokines and neurotrophic factors. BV2 microglia and primarily cultured astrocytes were transduced with C, N, F, and NF. Real-time PCR analyses were carried out 12 h after LPS (100 ng/ml, for pro-inflammatory cytokine expressions), IL-4 (10 ng/ml, other M2 markers), or without the treatment (neurotrophic factors). Significantly different from the control (C)*, N#, F‡ at P < 0.05, n = 3–6 PCRs; one-way ANOVA followed by Bonferroni post hoc test.B, C NO levels released (B) and arginase activity (C) were measured in the media and cells for BV-2 microglia cultures, respectively. Significantly different from the control (C)*, N#, F‡ at P < 0.05, n = 3 reactions, P-values: 0.027 (N-CM*), 0.033 (F-CM*), 0.018 (NF-CM*), and 0.033 (NF-CM‡) for the NO level, 0.011*, 0.025#, and 0.036‡ for the arginase activity; one-way ANOVA followed by Bonferroni post hoc test.

Mentions: We next sought to identify the paracrine factors responsible for the Nurr1- and Foxa2-mediated neuroprotection. Saijo et al (2009) have reported that knockdown of Nurr1 aggravated mDA neuronal death by increasing the production/release of pro-inflammatory cytokines from activated microglia. Consistent with this, we found that forced expression of Nurr1 in BV2 microglia led to a significant reduction in the expression of the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), inducible nitric oxide (NO) synthase (iNOS), and interleukin-1β (IL-1β) upon exposure to the Toll-like receptor 4 (TLR4) ligand, lipopolysaccharide (LPS) (Fig4A, upper). Interestingly, a decrease in pro-inflammatory cytokine expression was also evident in Foxa2-expressing microglia, indicating that Foxa2 alone, without interacting with Nurr1, can exert an anti-inflammatory action. Regulation of inflammatory responses by Foxa2 has also been shown in other tissues (Lappalainen et al, 2005; Tang et al, 2013). Importantly, Nurr1 and Foxa2 synergism was very dramatic, and transcripts of the pro-inflammatory cytokines were undetectable or barely detected after LPS treatment of Nurr1 + Foxa2-expressing BV2 cells (Fig4A, upper). In line with the gene expression results, NO levels in the CM from the Nurr1 + Foxa2-transduced microglia were lower than in the CM from control microglia (Fig4B). As well as microglia, astrocytes can create an inflammatory environment by releasing pro-inflammatory molecules (van Noort & Bsibsi, 2009; Gorina et al, 2011), and similar patterns of pro-inflammatory cytokine expression decrease were seen in primary astrocytes transduced with Nurr1 and Foxa2 (Fig4A, lower). S100β, a soluble protein released from astrocytes, acts as a damage-associated factor via receptor for advanced glycation end products (RAGE) pathways (Hofmann et al, 1999; Villarreal et al, 2011). Previous studies have shown that both S100β and RAGE increase in PD patients and MPTP-treated mice, and contribute to the damage to mDA neurons (Muramatsu et al, 2003; Sathe et al, 2012). We found that Nurr1 + Foxa2 expression in astrocytes significantly decreased S100β and RAGE levels (Fig4A, lower).


Combined Nurr1 and Foxa2 roles in the therapy of Parkinson's disease.

Oh SM, Chang MY, Song JJ, Rhee YH, Joe EH, Lee HS, Yi SH, Lee SH - EMBO Mol Med (2015)

Mechanisms for the paracrine neuroprotective roles by Nurr1- and Foxa2-expressing glial cellsA Real-time PCR analysis for pro-inflammatory cytokines and neurotrophic factors. BV2 microglia and primarily cultured astrocytes were transduced with C, N, F, and NF. Real-time PCR analyses were carried out 12 h after LPS (100 ng/ml, for pro-inflammatory cytokine expressions), IL-4 (10 ng/ml, other M2 markers), or without the treatment (neurotrophic factors). Significantly different from the control (C)*, N#, F‡ at P < 0.05, n = 3–6 PCRs; one-way ANOVA followed by Bonferroni post hoc test.B, C NO levels released (B) and arginase activity (C) were measured in the media and cells for BV-2 microglia cultures, respectively. Significantly different from the control (C)*, N#, F‡ at P < 0.05, n = 3 reactions, P-values: 0.027 (N-CM*), 0.033 (F-CM*), 0.018 (NF-CM*), and 0.033 (NF-CM‡) for the NO level, 0.011*, 0.025#, and 0.036‡ for the arginase activity; one-way ANOVA followed by Bonferroni post hoc test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig04: Mechanisms for the paracrine neuroprotective roles by Nurr1- and Foxa2-expressing glial cellsA Real-time PCR analysis for pro-inflammatory cytokines and neurotrophic factors. BV2 microglia and primarily cultured astrocytes were transduced with C, N, F, and NF. Real-time PCR analyses were carried out 12 h after LPS (100 ng/ml, for pro-inflammatory cytokine expressions), IL-4 (10 ng/ml, other M2 markers), or without the treatment (neurotrophic factors). Significantly different from the control (C)*, N#, F‡ at P < 0.05, n = 3–6 PCRs; one-way ANOVA followed by Bonferroni post hoc test.B, C NO levels released (B) and arginase activity (C) were measured in the media and cells for BV-2 microglia cultures, respectively. Significantly different from the control (C)*, N#, F‡ at P < 0.05, n = 3 reactions, P-values: 0.027 (N-CM*), 0.033 (F-CM*), 0.018 (NF-CM*), and 0.033 (NF-CM‡) for the NO level, 0.011*, 0.025#, and 0.036‡ for the arginase activity; one-way ANOVA followed by Bonferroni post hoc test.
Mentions: We next sought to identify the paracrine factors responsible for the Nurr1- and Foxa2-mediated neuroprotection. Saijo et al (2009) have reported that knockdown of Nurr1 aggravated mDA neuronal death by increasing the production/release of pro-inflammatory cytokines from activated microglia. Consistent with this, we found that forced expression of Nurr1 in BV2 microglia led to a significant reduction in the expression of the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), inducible nitric oxide (NO) synthase (iNOS), and interleukin-1β (IL-1β) upon exposure to the Toll-like receptor 4 (TLR4) ligand, lipopolysaccharide (LPS) (Fig4A, upper). Interestingly, a decrease in pro-inflammatory cytokine expression was also evident in Foxa2-expressing microglia, indicating that Foxa2 alone, without interacting with Nurr1, can exert an anti-inflammatory action. Regulation of inflammatory responses by Foxa2 has also been shown in other tissues (Lappalainen et al, 2005; Tang et al, 2013). Importantly, Nurr1 and Foxa2 synergism was very dramatic, and transcripts of the pro-inflammatory cytokines were undetectable or barely detected after LPS treatment of Nurr1 + Foxa2-expressing BV2 cells (Fig4A, upper). In line with the gene expression results, NO levels in the CM from the Nurr1 + Foxa2-transduced microglia were lower than in the CM from control microglia (Fig4B). As well as microglia, astrocytes can create an inflammatory environment by releasing pro-inflammatory molecules (van Noort & Bsibsi, 2009; Gorina et al, 2011), and similar patterns of pro-inflammatory cytokine expression decrease were seen in primary astrocytes transduced with Nurr1 and Foxa2 (Fig4A, lower). S100β, a soluble protein released from astrocytes, acts as a damage-associated factor via receptor for advanced glycation end products (RAGE) pathways (Hofmann et al, 1999; Villarreal et al, 2011). Previous studies have shown that both S100β and RAGE increase in PD patients and MPTP-treated mice, and contribute to the damage to mDA neurons (Muramatsu et al, 2003; Sathe et al, 2012). We found that Nurr1 + Foxa2 expression in astrocytes significantly decreased S100β and RAGE levels (Fig4A, lower).

Bottom Line: In addition to their proposed cell-autonomous actions in mDA neurons, forced expression of these factors in neighboring glia synergistically protects degenerating mDA neurons in a paracrine mode.As a consequence of these bimodal actions, adeno-associated virus (AAV)-mediated gene delivery of Nurr1 and Foxa2 in a PD mouse model markedly protected mDA neurons and motor behaviors associated with nigrostriatal DA neurotransmission.The effects of the combined gene delivery were dramatic, highly reproducible, and sustained for at least 1 year, suggesting that expression of these factors is a promising approach in PD therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.

No MeSH data available.


Related in: MedlinePlus