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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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PGC-1α expression protects against aSyn toxicity in the SNpc of male PGC1α-KO mice. PGC1α-KO mice were co-injected with two AAV2/6 vectors encoding for aSyn and PGC-1α (PGC1α + aSyn). The control group is injected with a non-coding vector instead of AAV-PGC-1α (NCV + aSyn). (a) Loss of TH-positive neurons in the SNpc at 6 months post-injection. PGC-1α overexpression induces significant protection against aSyn toxicity. Statistical analysis: Student’s t test; PGC1α + aSyn: n = 10; NCV + aSyn: n = 10; *p < 0.05. (b) Analysis according to gender shows that the protective effect of AAV-PGC-1α is specific to male mice. Statistical analysis: two-way ANOVA with Newman-Keuls post-hoc test; PGC1α + aSyn: n = 4 males and 6 females; NCV + aSyn: n = 5 males and 5 females; *p < 0.05. (c,d) Representative photomicrographs showing the loss of TH-positive neurons in the SNpc of NCV + aSyn mice (c), as compared to PGC1α + aSyn mice (d). The non-injected side (NInj) is shown for comparison. Scale bar: 500 μm. (e) Gender-specific analysis reveals significant protection of striatal TH fibers only in male mice PGC1α-KO mice injected with the AAV-PGC-1α vector. Statistical analysis as in (b); *p < 0.05 and #p = 0.058. (f) Stereological gender-specific analysis of the loss of Nissl-positive neurons in the SNpc. Statistical analysis as in (b): # p = 0.070, § p = 0.059.
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Fig8: PGC-1α expression protects against aSyn toxicity in the SNpc of male PGC1α-KO mice. PGC1α-KO mice were co-injected with two AAV2/6 vectors encoding for aSyn and PGC-1α (PGC1α + aSyn). The control group is injected with a non-coding vector instead of AAV-PGC-1α (NCV + aSyn). (a) Loss of TH-positive neurons in the SNpc at 6 months post-injection. PGC-1α overexpression induces significant protection against aSyn toxicity. Statistical analysis: Student’s t test; PGC1α + aSyn: n = 10; NCV + aSyn: n = 10; *p < 0.05. (b) Analysis according to gender shows that the protective effect of AAV-PGC-1α is specific to male mice. Statistical analysis: two-way ANOVA with Newman-Keuls post-hoc test; PGC1α + aSyn: n = 4 males and 6 females; NCV + aSyn: n = 5 males and 5 females; *p < 0.05. (c,d) Representative photomicrographs showing the loss of TH-positive neurons in the SNpc of NCV + aSyn mice (c), as compared to PGC1α + aSyn mice (d). The non-injected side (NInj) is shown for comparison. Scale bar: 500 μm. (e) Gender-specific analysis reveals significant protection of striatal TH fibers only in male mice PGC1α-KO mice injected with the AAV-PGC-1α vector. Statistical analysis as in (b); *p < 0.05 and #p = 0.058. (f) Stereological gender-specific analysis of the loss of Nissl-positive neurons in the SNpc. Statistical analysis as in (b): # p = 0.070, § p = 0.059.

Mentions: A gender-balanced cohort of young adult PGC1α-KO mice was co-injected in the SNpc with the optimized AAV2/6 vector encoding aSyn (1 × 107 TU), together with a control non-coding vector (5 × 106 TU). Six months post-injection, PGC1α-KO mice indeed showed a significant, 29.1 ± 4.3% loss of nigral TH-positive neurons in the ipsilateral SNpc (Figure 8a to c). In male mice, nigral degeneration induced by the optimized vector reached 34 ± 8.4% loss of TH-positive neurons, as compared to the non-injected side (Figure 8b). In female mice, the extent of dopaminergic neuron loss was slightly lower (25.8 ± 4.8%). With the optimized aSyn-expressing vector, neuronal loss in female mice was approximately twice higher than in our previous experiment (see Figure 4d), no more significantly different from their male counterparts. In the striatum, the effect on dopaminergic axons was also more pronounced. We measured an average loss of TH immunoreactivity of 22.7 ± 3.4% over the whole striatum, reaching 26.4 ± 7.4% in male, and 20.2 ± 3.1% in female mice (Figure 8e). To verify if the loss of the dopaminergic marker TH was indeed associated with neuronal degeneration, we performed stereological estimates of the number of Nissl-stained neuronal nuclei in the SNpc. We found an overall 18.7 ± 3.0% reduction in the number of neuronal nuclei in the injected SNpc (18.0 ± 6.0% in male and 17.1 ± 3.6% in female mice), consistent with aSyn-induced neuronal loss (Figure 8f).Figure 8


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)

PGC-1α expression protects against aSyn toxicity in the SNpc of male PGC1α-KO mice. PGC1α-KO mice were co-injected with two AAV2/6 vectors encoding for aSyn and PGC-1α (PGC1α + aSyn). The control group is injected with a non-coding vector instead of AAV-PGC-1α (NCV + aSyn). (a) Loss of TH-positive neurons in the SNpc at 6 months post-injection. PGC-1α overexpression induces significant protection against aSyn toxicity. Statistical analysis: Student’s t test; PGC1α + aSyn: n = 10; NCV + aSyn: n = 10; *p < 0.05. (b) Analysis according to gender shows that the protective effect of AAV-PGC-1α is specific to male mice. Statistical analysis: two-way ANOVA with Newman-Keuls post-hoc test; PGC1α + aSyn: n = 4 males and 6 females; NCV + aSyn: n = 5 males and 5 females; *p < 0.05. (c,d) Representative photomicrographs showing the loss of TH-positive neurons in the SNpc of NCV + aSyn mice (c), as compared to PGC1α + aSyn mice (d). The non-injected side (NInj) is shown for comparison. Scale bar: 500 μm. (e) Gender-specific analysis reveals significant protection of striatal TH fibers only in male mice PGC1α-KO mice injected with the AAV-PGC-1α vector. Statistical analysis as in (b); *p < 0.05 and #p = 0.058. (f) Stereological gender-specific analysis of the loss of Nissl-positive neurons in the SNpc. Statistical analysis as in (b): # p = 0.070, § p = 0.059.
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Fig8: PGC-1α expression protects against aSyn toxicity in the SNpc of male PGC1α-KO mice. PGC1α-KO mice were co-injected with two AAV2/6 vectors encoding for aSyn and PGC-1α (PGC1α + aSyn). The control group is injected with a non-coding vector instead of AAV-PGC-1α (NCV + aSyn). (a) Loss of TH-positive neurons in the SNpc at 6 months post-injection. PGC-1α overexpression induces significant protection against aSyn toxicity. Statistical analysis: Student’s t test; PGC1α + aSyn: n = 10; NCV + aSyn: n = 10; *p < 0.05. (b) Analysis according to gender shows that the protective effect of AAV-PGC-1α is specific to male mice. Statistical analysis: two-way ANOVA with Newman-Keuls post-hoc test; PGC1α + aSyn: n = 4 males and 6 females; NCV + aSyn: n = 5 males and 5 females; *p < 0.05. (c,d) Representative photomicrographs showing the loss of TH-positive neurons in the SNpc of NCV + aSyn mice (c), as compared to PGC1α + aSyn mice (d). The non-injected side (NInj) is shown for comparison. Scale bar: 500 μm. (e) Gender-specific analysis reveals significant protection of striatal TH fibers only in male mice PGC1α-KO mice injected with the AAV-PGC-1α vector. Statistical analysis as in (b); *p < 0.05 and #p = 0.058. (f) Stereological gender-specific analysis of the loss of Nissl-positive neurons in the SNpc. Statistical analysis as in (b): # p = 0.070, § p = 0.059.
Mentions: A gender-balanced cohort of young adult PGC1α-KO mice was co-injected in the SNpc with the optimized AAV2/6 vector encoding aSyn (1 × 107 TU), together with a control non-coding vector (5 × 106 TU). Six months post-injection, PGC1α-KO mice indeed showed a significant, 29.1 ± 4.3% loss of nigral TH-positive neurons in the ipsilateral SNpc (Figure 8a to c). In male mice, nigral degeneration induced by the optimized vector reached 34 ± 8.4% loss of TH-positive neurons, as compared to the non-injected side (Figure 8b). In female mice, the extent of dopaminergic neuron loss was slightly lower (25.8 ± 4.8%). With the optimized aSyn-expressing vector, neuronal loss in female mice was approximately twice higher than in our previous experiment (see Figure 4d), no more significantly different from their male counterparts. In the striatum, the effect on dopaminergic axons was also more pronounced. We measured an average loss of TH immunoreactivity of 22.7 ± 3.4% over the whole striatum, reaching 26.4 ± 7.4% in male, and 20.2 ± 3.1% in female mice (Figure 8e). To verify if the loss of the dopaminergic marker TH was indeed associated with neuronal degeneration, we performed stereological estimates of the number of Nissl-stained neuronal nuclei in the SNpc. We found an overall 18.7 ± 3.0% reduction in the number of neuronal nuclei in the injected SNpc (18.0 ± 6.0% in male and 17.1 ± 3.6% in female mice), consistent with aSyn-induced neuronal loss (Figure 8f).Figure 8

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