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PGC-1α activity in nigral dopamine neurons determines vulnerability to α-synuclein.

Ciron C, Zheng L, Bobela W, Knott GW, Leone TC, Kelly DP, Schneider BL - Acta Neuropathol Commun (2015)

Bottom Line: Mitochondrial dysfunction and oxidative stress are critical factors in the pathogenesis of age-dependent neurodegenerative diseases.PGC-1α, a master regulator of mitochondrial biogenesis and cellular antioxidant defense, has emerged as a possible therapeutic target for Parkinson's disease, with important roles in the function and survival of dopaminergic neurons in the substantia nigra.The objective of this study is to determine if the loss of PGC-1α activity contributes to α-synuclein-induced degeneration.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Mitochondrial dysfunction and oxidative stress are critical factors in the pathogenesis of age-dependent neurodegenerative diseases. PGC-1α, a master regulator of mitochondrial biogenesis and cellular antioxidant defense, has emerged as a possible therapeutic target for Parkinson's disease, with important roles in the function and survival of dopaminergic neurons in the substantia nigra. The objective of this study is to determine if the loss of PGC-1α activity contributes to α-synuclein-induced degeneration.

Results: We explore the vulnerability of PGC-1α mice to the accumulation of human α-synuclein in nigral neurons, and assess the neuroprotective effect of AAV-mediated PGC-1α expression in this experimental model. Using neuronal cultures derived from these mice, mitochondrial respiration and production of reactive oxygen species are assessed in conditions of human α-synuclein overexpression. We find ultrastructural evidence for abnormal mitochondria and fragmented endoplasmic reticulum in the nigral dopaminergic neurons of PGC-1α mice. Furthermore, PGC-1α nigral neurons are more prone to degenerate following overexpression of human α-synuclein, an effect more apparent in male mice. PGC-1α overexpression restores mitochondrial morphology, oxidative stress detoxification and basal respiration, which is consistent with the observed neuroprotection against α-synuclein toxicity in male PGC-1α mice.

Conclusions: Altogether, our results highlight an important role for PGC-1α in controlling the mitochondrial function of nigral neurons accumulating α-synuclein, which may be critical for gender-dependent vulnerability to Parkinson's disease.

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Expression of PGC-1α rescues ER morphology in PGC1α-KO mice, and increases the number of mitochondrial contacts with ER. (a) Electron micrographs of neuronal soma in the SNpc of PGC1α-KO, PGC1α Inj and WT mice. Black arrowheads indicate the presence of giant mitochondria with disorganized cristae. (b) ER cisternae are colored in light gray. The cell membrane at the border of the neuronal cytosol is outlined. Note that PGC1α-KO mice display a disorganized and fragmented ER. In WT and PGC1α Inj mice, normal ER stacks are observed. Scale bar: 1 μm. (c,d) Quantification of the median length of ER profiles and number of branch points per μm of ER. (e) Relative length distribution of the ER segments in individual neurons from WT, PGC1α-KO and PGC1α Inj mice. Note the overall fragmentation of the ER in neurons from PGC1α-KO mice. Statistical analysis for c-d: one-way ANOVA with Newman-Keuls post-hoc test; WT: n = 51 neurons; PGC1α-KO: n = 51 neurons; PGC1α Inj: n = 60 neurons (f) Percentage of mitochondria having membrane contacts with ER. Note that PGC-1α significant increases the proportion of mitochondria with ER contacts. Statistical analysis: one-way ANOVA with Newman-Keuls post-hoc test; WT: n = 79 neurons; PGC1α-KO: n = 89 neurons; PGC1α Inj: n = 113 neurons; *p < 0.05, **p < 0.001 and ***p < 0.001. Micrographs were obtained from 3 animals in each group.
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Fig3: Expression of PGC-1α rescues ER morphology in PGC1α-KO mice, and increases the number of mitochondrial contacts with ER. (a) Electron micrographs of neuronal soma in the SNpc of PGC1α-KO, PGC1α Inj and WT mice. Black arrowheads indicate the presence of giant mitochondria with disorganized cristae. (b) ER cisternae are colored in light gray. The cell membrane at the border of the neuronal cytosol is outlined. Note that PGC1α-KO mice display a disorganized and fragmented ER. In WT and PGC1α Inj mice, normal ER stacks are observed. Scale bar: 1 μm. (c,d) Quantification of the median length of ER profiles and number of branch points per μm of ER. (e) Relative length distribution of the ER segments in individual neurons from WT, PGC1α-KO and PGC1α Inj mice. Note the overall fragmentation of the ER in neurons from PGC1α-KO mice. Statistical analysis for c-d: one-way ANOVA with Newman-Keuls post-hoc test; WT: n = 51 neurons; PGC1α-KO: n = 51 neurons; PGC1α Inj: n = 60 neurons (f) Percentage of mitochondria having membrane contacts with ER. Note that PGC-1α significant increases the proportion of mitochondria with ER contacts. Statistical analysis: one-way ANOVA with Newman-Keuls post-hoc test; WT: n = 79 neurons; PGC1α-KO: n = 89 neurons; PGC1α Inj: n = 113 neurons; *p < 0.05, **p < 0.001 and ***p < 0.001. Micrographs were obtained from 3 animals in each group.

Mentions: As functional interactions exist between mitochondria and ER, we examined ER morphology in the soma of dopaminergic neurons in the SNpc (Figure 3). WT mice displayed a normal, parallel-organized ER stack. In stark contrast, the ER of PGC1α-KO mice appeared disorganized and fragmented (Figure 3a and b). In PGC1α-KO mice, we measured in neuronal cells a significant reduction in the median length of ER segments and a significant decrease in the number of ER branches compared to WT animals (Figure 3c and d). By analyzing more closely the size distribution of ER segments, we found a significant increase in the percentage of small ER segments with a length ≤0.25 μm, and a corresponding decrease in ER segments between 0.5 and 1 μm in PGC1α-KO mice compared to WT mice (Figure 3e). Both of these defects were significantly rescued by AAV-mediated expression of PGC-1α (Figure 3e). Next, we examined membrane contacts between mitochondria and ER (Figure 3f). Theses interactions are crucial in a number of physiological processes, including mitochondrial function, mitochondrial biogenesis, lipid metabolism, Ca2+ signaling and cell death [36]. As compared to WT and PGC1α-KO mice, we observed a significant increase in the proportion of mitochondria making membrane contacts with the ER in animals injected with the AAV-PGC-1α vector, further highlighting the role of PGC-1α in controlling ER/mitochondria interactions.Figure 3


PGC-1α activity in nigral dopamine neurons determines vulnerability to α-synuclein.

Ciron C, Zheng L, Bobela W, Knott GW, Leone TC, Kelly DP, Schneider BL - Acta Neuropathol Commun (2015)

Expression of PGC-1α rescues ER morphology in PGC1α-KO mice, and increases the number of mitochondrial contacts with ER. (a) Electron micrographs of neuronal soma in the SNpc of PGC1α-KO, PGC1α Inj and WT mice. Black arrowheads indicate the presence of giant mitochondria with disorganized cristae. (b) ER cisternae are colored in light gray. The cell membrane at the border of the neuronal cytosol is outlined. Note that PGC1α-KO mice display a disorganized and fragmented ER. In WT and PGC1α Inj mice, normal ER stacks are observed. Scale bar: 1 μm. (c,d) Quantification of the median length of ER profiles and number of branch points per μm of ER. (e) Relative length distribution of the ER segments in individual neurons from WT, PGC1α-KO and PGC1α Inj mice. Note the overall fragmentation of the ER in neurons from PGC1α-KO mice. Statistical analysis for c-d: one-way ANOVA with Newman-Keuls post-hoc test; WT: n = 51 neurons; PGC1α-KO: n = 51 neurons; PGC1α Inj: n = 60 neurons (f) Percentage of mitochondria having membrane contacts with ER. Note that PGC-1α significant increases the proportion of mitochondria with ER contacts. Statistical analysis: one-way ANOVA with Newman-Keuls post-hoc test; WT: n = 79 neurons; PGC1α-KO: n = 89 neurons; PGC1α Inj: n = 113 neurons; *p < 0.05, **p < 0.001 and ***p < 0.001. Micrographs were obtained from 3 animals in each group.
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Related In: Results  -  Collection

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Fig3: Expression of PGC-1α rescues ER morphology in PGC1α-KO mice, and increases the number of mitochondrial contacts with ER. (a) Electron micrographs of neuronal soma in the SNpc of PGC1α-KO, PGC1α Inj and WT mice. Black arrowheads indicate the presence of giant mitochondria with disorganized cristae. (b) ER cisternae are colored in light gray. The cell membrane at the border of the neuronal cytosol is outlined. Note that PGC1α-KO mice display a disorganized and fragmented ER. In WT and PGC1α Inj mice, normal ER stacks are observed. Scale bar: 1 μm. (c,d) Quantification of the median length of ER profiles and number of branch points per μm of ER. (e) Relative length distribution of the ER segments in individual neurons from WT, PGC1α-KO and PGC1α Inj mice. Note the overall fragmentation of the ER in neurons from PGC1α-KO mice. Statistical analysis for c-d: one-way ANOVA with Newman-Keuls post-hoc test; WT: n = 51 neurons; PGC1α-KO: n = 51 neurons; PGC1α Inj: n = 60 neurons (f) Percentage of mitochondria having membrane contacts with ER. Note that PGC-1α significant increases the proportion of mitochondria with ER contacts. Statistical analysis: one-way ANOVA with Newman-Keuls post-hoc test; WT: n = 79 neurons; PGC1α-KO: n = 89 neurons; PGC1α Inj: n = 113 neurons; *p < 0.05, **p < 0.001 and ***p < 0.001. Micrographs were obtained from 3 animals in each group.
Mentions: As functional interactions exist between mitochondria and ER, we examined ER morphology in the soma of dopaminergic neurons in the SNpc (Figure 3). WT mice displayed a normal, parallel-organized ER stack. In stark contrast, the ER of PGC1α-KO mice appeared disorganized and fragmented (Figure 3a and b). In PGC1α-KO mice, we measured in neuronal cells a significant reduction in the median length of ER segments and a significant decrease in the number of ER branches compared to WT animals (Figure 3c and d). By analyzing more closely the size distribution of ER segments, we found a significant increase in the percentage of small ER segments with a length ≤0.25 μm, and a corresponding decrease in ER segments between 0.5 and 1 μm in PGC1α-KO mice compared to WT mice (Figure 3e). Both of these defects were significantly rescued by AAV-mediated expression of PGC-1α (Figure 3e). Next, we examined membrane contacts between mitochondria and ER (Figure 3f). Theses interactions are crucial in a number of physiological processes, including mitochondrial function, mitochondrial biogenesis, lipid metabolism, Ca2+ signaling and cell death [36]. As compared to WT and PGC1α-KO mice, we observed a significant increase in the proportion of mitochondria making membrane contacts with the ER in animals injected with the AAV-PGC-1α vector, further highlighting the role of PGC-1α in controlling ER/mitochondria interactions.Figure 3

Bottom Line: Mitochondrial dysfunction and oxidative stress are critical factors in the pathogenesis of age-dependent neurodegenerative diseases.PGC-1α, a master regulator of mitochondrial biogenesis and cellular antioxidant defense, has emerged as a possible therapeutic target for Parkinson's disease, with important roles in the function and survival of dopaminergic neurons in the substantia nigra.The objective of this study is to determine if the loss of PGC-1α activity contributes to α-synuclein-induced degeneration.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Mitochondrial dysfunction and oxidative stress are critical factors in the pathogenesis of age-dependent neurodegenerative diseases. PGC-1α, a master regulator of mitochondrial biogenesis and cellular antioxidant defense, has emerged as a possible therapeutic target for Parkinson's disease, with important roles in the function and survival of dopaminergic neurons in the substantia nigra. The objective of this study is to determine if the loss of PGC-1α activity contributes to α-synuclein-induced degeneration.

Results: We explore the vulnerability of PGC-1α mice to the accumulation of human α-synuclein in nigral neurons, and assess the neuroprotective effect of AAV-mediated PGC-1α expression in this experimental model. Using neuronal cultures derived from these mice, mitochondrial respiration and production of reactive oxygen species are assessed in conditions of human α-synuclein overexpression. We find ultrastructural evidence for abnormal mitochondria and fragmented endoplasmic reticulum in the nigral dopaminergic neurons of PGC-1α mice. Furthermore, PGC-1α nigral neurons are more prone to degenerate following overexpression of human α-synuclein, an effect more apparent in male mice. PGC-1α overexpression restores mitochondrial morphology, oxidative stress detoxification and basal respiration, which is consistent with the observed neuroprotection against α-synuclein toxicity in male PGC-1α mice.

Conclusions: Altogether, our results highlight an important role for PGC-1α in controlling the mitochondrial function of nigral neurons accumulating α-synuclein, which may be critical for gender-dependent vulnerability to Parkinson's disease.

Show MeSH
Related in: MedlinePlus