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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

Reduction of Nurr1 and Foxa2 in mDA neurons during aging and degenerationA–C Nurr1 and Foxa2 protein levels in mDA neurons decrease in the midbrains of old mice in vivo (A) and in vitro after long-term culture (B and C). (A) Nurr1 and Foxa2 protein levels were compared in individual mDA neurons of the midbrains of young (10 weeks) and old mice (18 months) of the same mouse strain (C57BL/6, male). All the midbrain sections were immunofluorescently co-stained with Nurr1/TH (upper) and Foxa2/TH (lower) under identical conditions, and levels of Nurr1 and Foxa2 proteins were determined in individual TH+ mDA neurons by measuring mean fluorescence intensities (MFI) using LAS image analysis (Leica). Dots in the graphs represent the Nurr1 and Foxa2 MFI values of individual TH+ DA neurons in the SN of each animal. The average MFI values (indicated by horizontal lines) of three animals from each group were compared (***P = 5.25E-88 for Nurr1 intensity, 5.57E-40 for Foxa2 intensity, one-way ANOVA followed by Bonferroni post hoc test). Nurr1 and Foxa2 protein levels were also quantified in cultured mDA neurons over 6–34 days in vitro by Western blotting (B) and by immunocytochemical analysis (C). Significantly lower MFI values on day 24 of culture (D24) compared to D12 at *P = 0.027 (Nurr1), *P = 0.012 (Foxa2), n = 60–70 TH+ cells from two cultures in each group, unpaired Student's t-test.D, E Loss of Nurr1 and Foxa2 expression in mDA neurons after treatment with the neurotoxin MPTP (or MPP+). Mice (10 weeks old) were treated with MPTP for 5 days as described in Materials and Methods. Three days after the last MPTP injection, Nurr1 and Foxa2 protein levels in the TH+ mDA neurons of the MPTP-treated SN were compared with in the mDA neurons of untreated mice (D) (***P = 5.47E-103 for Nurr1 intensity, 1.53E-111 for Foxa2 intensity, one-way ANOVA followed by Bonferroni post hoc test.). The effects of neurotoxin treatment were also determined in mDA neuron cultures treated with MPP+ (250 μM, 8 h, E). *P = 0.015 (% Nurr1+/TH+ cells), *P = 0.018 (% Foxa2+/TH+ cells), unpaired Student's t-test.
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fig02: Reduction of Nurr1 and Foxa2 in mDA neurons during aging and degenerationA–C Nurr1 and Foxa2 protein levels in mDA neurons decrease in the midbrains of old mice in vivo (A) and in vitro after long-term culture (B and C). (A) Nurr1 and Foxa2 protein levels were compared in individual mDA neurons of the midbrains of young (10 weeks) and old mice (18 months) of the same mouse strain (C57BL/6, male). All the midbrain sections were immunofluorescently co-stained with Nurr1/TH (upper) and Foxa2/TH (lower) under identical conditions, and levels of Nurr1 and Foxa2 proteins were determined in individual TH+ mDA neurons by measuring mean fluorescence intensities (MFI) using LAS image analysis (Leica). Dots in the graphs represent the Nurr1 and Foxa2 MFI values of individual TH+ DA neurons in the SN of each animal. The average MFI values (indicated by horizontal lines) of three animals from each group were compared (***P = 5.25E-88 for Nurr1 intensity, 5.57E-40 for Foxa2 intensity, one-way ANOVA followed by Bonferroni post hoc test). Nurr1 and Foxa2 protein levels were also quantified in cultured mDA neurons over 6–34 days in vitro by Western blotting (B) and by immunocytochemical analysis (C). Significantly lower MFI values on day 24 of culture (D24) compared to D12 at *P = 0.027 (Nurr1), *P = 0.012 (Foxa2), n = 60–70 TH+ cells from two cultures in each group, unpaired Student's t-test.D, E Loss of Nurr1 and Foxa2 expression in mDA neurons after treatment with the neurotoxin MPTP (or MPP+). Mice (10 weeks old) were treated with MPTP for 5 days as described in Materials and Methods. Three days after the last MPTP injection, Nurr1 and Foxa2 protein levels in the TH+ mDA neurons of the MPTP-treated SN were compared with in the mDA neurons of untreated mice (D) (***P = 5.47E-103 for Nurr1 intensity, 1.53E-111 for Foxa2 intensity, one-way ANOVA followed by Bonferroni post hoc test.). The effects of neurotoxin treatment were also determined in mDA neuron cultures treated with MPP+ (250 μM, 8 h, E). *P = 0.015 (% Nurr1+/TH+ cells), *P = 0.018 (% Foxa2+/TH+ cells), unpaired Student's t-test.

Mentions: Aging is a crucial predisposing factor for PD (Moghal et al, 1994). Interestingly, both Nurr1 and Foxa2 levels were significantly lower in the individual mDA neurons of old mice (18 months) than in their young counterparts (10 weeks) (Fig2A). In agreement with this, Nurr1 and Foxa2 levels also gradually declined in cultured mDA neurons during the late period of culture (6–34 days after onset of differentiation in vitro; Fig2B), ultimately giving rise to abundant TH+ cells negative for Nurr1/Foxa2 (% Nurr1+ of TH+ cells: 90.5% at D12 versus 14.3% at D24 and %Foxa2+ of TH+ cells: 91.3% at D12 versus 12.9% at D24, Fig2C). These findings are consistent with the decreased Nurr1 levels in the SN of elderly persons (Chu et al, 2002) and also imply that loss of Foxa2 is an additional aspect of the aging process in mDA neurons.


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)

Reduction of Nurr1 and Foxa2 in mDA neurons during aging and degenerationA–C Nurr1 and Foxa2 protein levels in mDA neurons decrease in the midbrains of old mice in vivo (A) and in vitro after long-term culture (B and C). (A) Nurr1 and Foxa2 protein levels were compared in individual mDA neurons of the midbrains of young (10 weeks) and old mice (18 months) of the same mouse strain (C57BL/6, male). All the midbrain sections were immunofluorescently co-stained with Nurr1/TH (upper) and Foxa2/TH (lower) under identical conditions, and levels of Nurr1 and Foxa2 proteins were determined in individual TH+ mDA neurons by measuring mean fluorescence intensities (MFI) using LAS image analysis (Leica). Dots in the graphs represent the Nurr1 and Foxa2 MFI values of individual TH+ DA neurons in the SN of each animal. The average MFI values (indicated by horizontal lines) of three animals from each group were compared (***P = 5.25E-88 for Nurr1 intensity, 5.57E-40 for Foxa2 intensity, one-way ANOVA followed by Bonferroni post hoc test). Nurr1 and Foxa2 protein levels were also quantified in cultured mDA neurons over 6–34 days in vitro by Western blotting (B) and by immunocytochemical analysis (C). Significantly lower MFI values on day 24 of culture (D24) compared to D12 at *P = 0.027 (Nurr1), *P = 0.012 (Foxa2), n = 60–70 TH+ cells from two cultures in each group, unpaired Student's t-test.D, E Loss of Nurr1 and Foxa2 expression in mDA neurons after treatment with the neurotoxin MPTP (or MPP+). Mice (10 weeks old) were treated with MPTP for 5 days as described in Materials and Methods. Three days after the last MPTP injection, Nurr1 and Foxa2 protein levels in the TH+ mDA neurons of the MPTP-treated SN were compared with in the mDA neurons of untreated mice (D) (***P = 5.47E-103 for Nurr1 intensity, 1.53E-111 for Foxa2 intensity, one-way ANOVA followed by Bonferroni post hoc test.). The effects of neurotoxin treatment were also determined in mDA neuron cultures treated with MPP+ (250 μM, 8 h, E). *P = 0.015 (% Nurr1+/TH+ cells), *P = 0.018 (% Foxa2+/TH+ cells), unpaired Student's t-test.
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fig02: Reduction of Nurr1 and Foxa2 in mDA neurons during aging and degenerationA–C Nurr1 and Foxa2 protein levels in mDA neurons decrease in the midbrains of old mice in vivo (A) and in vitro after long-term culture (B and C). (A) Nurr1 and Foxa2 protein levels were compared in individual mDA neurons of the midbrains of young (10 weeks) and old mice (18 months) of the same mouse strain (C57BL/6, male). All the midbrain sections were immunofluorescently co-stained with Nurr1/TH (upper) and Foxa2/TH (lower) under identical conditions, and levels of Nurr1 and Foxa2 proteins were determined in individual TH+ mDA neurons by measuring mean fluorescence intensities (MFI) using LAS image analysis (Leica). Dots in the graphs represent the Nurr1 and Foxa2 MFI values of individual TH+ DA neurons in the SN of each animal. The average MFI values (indicated by horizontal lines) of three animals from each group were compared (***P = 5.25E-88 for Nurr1 intensity, 5.57E-40 for Foxa2 intensity, one-way ANOVA followed by Bonferroni post hoc test). Nurr1 and Foxa2 protein levels were also quantified in cultured mDA neurons over 6–34 days in vitro by Western blotting (B) and by immunocytochemical analysis (C). Significantly lower MFI values on day 24 of culture (D24) compared to D12 at *P = 0.027 (Nurr1), *P = 0.012 (Foxa2), n = 60–70 TH+ cells from two cultures in each group, unpaired Student's t-test.D, E Loss of Nurr1 and Foxa2 expression in mDA neurons after treatment with the neurotoxin MPTP (or MPP+). Mice (10 weeks old) were treated with MPTP for 5 days as described in Materials and Methods. Three days after the last MPTP injection, Nurr1 and Foxa2 protein levels in the TH+ mDA neurons of the MPTP-treated SN were compared with in the mDA neurons of untreated mice (D) (***P = 5.47E-103 for Nurr1 intensity, 1.53E-111 for Foxa2 intensity, one-way ANOVA followed by Bonferroni post hoc test.). The effects of neurotoxin treatment were also determined in mDA neuron cultures treated with MPP+ (250 μM, 8 h, E). *P = 0.015 (% Nurr1+/TH+ cells), *P = 0.018 (% Foxa2+/TH+ cells), unpaired Student's t-test.
Mentions: Aging is a crucial predisposing factor for PD (Moghal et al, 1994). Interestingly, both Nurr1 and Foxa2 levels were significantly lower in the individual mDA neurons of old mice (18 months) than in their young counterparts (10 weeks) (Fig2A). In agreement with this, Nurr1 and Foxa2 levels also gradually declined in cultured mDA neurons during the late period of culture (6–34 days after onset of differentiation in vitro; Fig2B), ultimately giving rise to abundant TH+ cells negative for Nurr1/Foxa2 (% Nurr1+ of TH+ cells: 90.5% at D12 versus 14.3% at D24 and %Foxa2+ of TH+ cells: 91.3% at D12 versus 12.9% at D24, Fig2C). These findings are consistent with the decreased Nurr1 levels in the SN of elderly persons (Chu et al, 2002) and also imply that loss of Foxa2 is an additional aspect of the aging process in mDA neurons.

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