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Sustained expression of PGC-1α in the rat nigrostriatal system selectively impairs dopaminergic function.

Ciron C, Lengacher S, Dusonchet J, Aebischer P, Schneider BL - Hum. Mol. Genet. (2012)

Bottom Line: In the adult rat nigrostriatal system, adeno-associated virus (AAV)-mediated overexpression of PGC-1α induces the selective loss of dopaminergic markers and increases dopamine (DA) catabolism, leading to a reduction in striatal DA content.Finally, PGC-1α overexpression does not prevent nigrostriatal degeneration in pathologic conditions induced by α-synuclein overexpression.These results highlight the central role of PGC-1α in the function and survival of dopaminergic neurons and the critical need for maintaining physiological levels of PGC-1α activity.

View Article: PubMed Central - PubMed

Affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

ABSTRACT
Mitochondrial dysfunction and oxidative stress have been implicated in the etiology of Parkinson's disease. Therefore, pathways controlling mitochondrial activity rapidly emerge as potential therapeutic targets. Here, we explore the neuronal response to prolonged overexpression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), a transcriptional regulator of mitochondrial function, both in vitro and in vivo. In neuronal primary cultures from the ventral midbrain, PGC-1α induces mitochondrial biogenesis and increases basal respiration. Over time, we observe an increasing proportion of the oxygen consumed by neurons which are dedicated to adenosine triphosphate production. In parallel to enhanced oxidative phosphorylation, PGC-1α progressively leads to a decrease in mitochondrial polarization. In the adult rat nigrostriatal system, adeno-associated virus (AAV)-mediated overexpression of PGC-1α induces the selective loss of dopaminergic markers and increases dopamine (DA) catabolism, leading to a reduction in striatal DA content. In addition, PGC-1α prevents the labeling of nigral neurons following striatal injection of the fluorogold retrograde tracer. When PGC-1α is expressed at higher levels following intranigral AAV injection, it leads to overt degeneration of dopaminergic neurons. Finally, PGC-1α overexpression does not prevent nigrostriatal degeneration in pathologic conditions induced by α-synuclein overexpression. Overall, we find that lasting overexpression of PGC-1α leads to major alterations in the metabolic activity of neuronal cells which dramatically impair dopaminergic function in vivo. These results highlight the central role of PGC-1α in the function and survival of dopaminergic neurons and the critical need for maintaining physiological levels of PGC-1α activity.

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Depletion of DA and metabolites and increased DA turnover. (A) Total striatal content of DA, DOPAC and HVA in the non-injected and injected hemispheres of PGC1 Lo and NCV Lo rats at 3 months post-injection. Results are expressed as the ratio of metabolite concentration in the injected versus non-injected hemisphere. Note the significant decrease in striatal levels of DA and metabolites in PGC1 Lo rats. Student's t-test: NCV Lo: n = 2, PGC1 Lo: n = 5; *P < 0.05, ***P < 0.001. (B) PGC1 Lo rats show higher DA turnover. DA turnover is determined as ([DOPAC]+[HVA])/[DA]. Student's t-test: NCV Lo, n = 2; PGC1 Lo, n = 5, **P < 0.01.
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DDR618F7: Depletion of DA and metabolites and increased DA turnover. (A) Total striatal content of DA, DOPAC and HVA in the non-injected and injected hemispheres of PGC1 Lo and NCV Lo rats at 3 months post-injection. Results are expressed as the ratio of metabolite concentration in the injected versus non-injected hemisphere. Note the significant decrease in striatal levels of DA and metabolites in PGC1 Lo rats. Student's t-test: NCV Lo: n = 2, PGC1 Lo: n = 5; *P < 0.05, ***P < 0.001. (B) PGC1 Lo rats show higher DA turnover. DA turnover is determined as ([DOPAC]+[HVA])/[DA]. Student's t-test: NCV Lo, n = 2; PGC1 Lo, n = 5, **P < 0.01.

Mentions: The level of DA and its metabolites were determined in extracts from striatal tissue. We compared rats injected in the striatum with either the PGC-1α vector, leading to a 4.5-fold increase in the level of PGC-1α mRNA in the SNpc (Table 1), or a control non-coding vector (AAV2/6-NCV), both at a dose of 6 × 107 TUs. When compared with the non-injected hemisphere, we measured a clear reduction in the striatal DA level (42.9 ± 1.7%) only in the PGC1 Lo group (Fig. 7A), consistent with the loss in TH expression. The levels of the DA metabolites DOPAC (74.6 ± 3.3%) and HVA (56.6 ± 3.2%) appeared to be further reduced when compared with the non-injected hemisphere. In the control group injected with a non-coding vector, the level of DA and metabolites remained similar in both the injected and non-injected striata.Figure 7.


Sustained expression of PGC-1α in the rat nigrostriatal system selectively impairs dopaminergic function.

Ciron C, Lengacher S, Dusonchet J, Aebischer P, Schneider BL - Hum. Mol. Genet. (2012)

Depletion of DA and metabolites and increased DA turnover. (A) Total striatal content of DA, DOPAC and HVA in the non-injected and injected hemispheres of PGC1 Lo and NCV Lo rats at 3 months post-injection. Results are expressed as the ratio of metabolite concentration in the injected versus non-injected hemisphere. Note the significant decrease in striatal levels of DA and metabolites in PGC1 Lo rats. Student's t-test: NCV Lo: n = 2, PGC1 Lo: n = 5; *P < 0.05, ***P < 0.001. (B) PGC1 Lo rats show higher DA turnover. DA turnover is determined as ([DOPAC]+[HVA])/[DA]. Student's t-test: NCV Lo, n = 2; PGC1 Lo, n = 5, **P < 0.01.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3313800&req=5

DDR618F7: Depletion of DA and metabolites and increased DA turnover. (A) Total striatal content of DA, DOPAC and HVA in the non-injected and injected hemispheres of PGC1 Lo and NCV Lo rats at 3 months post-injection. Results are expressed as the ratio of metabolite concentration in the injected versus non-injected hemisphere. Note the significant decrease in striatal levels of DA and metabolites in PGC1 Lo rats. Student's t-test: NCV Lo: n = 2, PGC1 Lo: n = 5; *P < 0.05, ***P < 0.001. (B) PGC1 Lo rats show higher DA turnover. DA turnover is determined as ([DOPAC]+[HVA])/[DA]. Student's t-test: NCV Lo, n = 2; PGC1 Lo, n = 5, **P < 0.01.
Mentions: The level of DA and its metabolites were determined in extracts from striatal tissue. We compared rats injected in the striatum with either the PGC-1α vector, leading to a 4.5-fold increase in the level of PGC-1α mRNA in the SNpc (Table 1), or a control non-coding vector (AAV2/6-NCV), both at a dose of 6 × 107 TUs. When compared with the non-injected hemisphere, we measured a clear reduction in the striatal DA level (42.9 ± 1.7%) only in the PGC1 Lo group (Fig. 7A), consistent with the loss in TH expression. The levels of the DA metabolites DOPAC (74.6 ± 3.3%) and HVA (56.6 ± 3.2%) appeared to be further reduced when compared with the non-injected hemisphere. In the control group injected with a non-coding vector, the level of DA and metabolites remained similar in both the injected and non-injected striata.Figure 7.

Bottom Line: In the adult rat nigrostriatal system, adeno-associated virus (AAV)-mediated overexpression of PGC-1α induces the selective loss of dopaminergic markers and increases dopamine (DA) catabolism, leading to a reduction in striatal DA content.Finally, PGC-1α overexpression does not prevent nigrostriatal degeneration in pathologic conditions induced by α-synuclein overexpression.These results highlight the central role of PGC-1α in the function and survival of dopaminergic neurons and the critical need for maintaining physiological levels of PGC-1α activity.

View Article: PubMed Central - PubMed

Affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

ABSTRACT
Mitochondrial dysfunction and oxidative stress have been implicated in the etiology of Parkinson's disease. Therefore, pathways controlling mitochondrial activity rapidly emerge as potential therapeutic targets. Here, we explore the neuronal response to prolonged overexpression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), a transcriptional regulator of mitochondrial function, both in vitro and in vivo. In neuronal primary cultures from the ventral midbrain, PGC-1α induces mitochondrial biogenesis and increases basal respiration. Over time, we observe an increasing proportion of the oxygen consumed by neurons which are dedicated to adenosine triphosphate production. In parallel to enhanced oxidative phosphorylation, PGC-1α progressively leads to a decrease in mitochondrial polarization. In the adult rat nigrostriatal system, adeno-associated virus (AAV)-mediated overexpression of PGC-1α induces the selective loss of dopaminergic markers and increases dopamine (DA) catabolism, leading to a reduction in striatal DA content. In addition, PGC-1α prevents the labeling of nigral neurons following striatal injection of the fluorogold retrograde tracer. When PGC-1α is expressed at higher levels following intranigral AAV injection, it leads to overt degeneration of dopaminergic neurons. Finally, PGC-1α overexpression does not prevent nigrostriatal degeneration in pathologic conditions induced by α-synuclein overexpression. Overall, we find that lasting overexpression of PGC-1α leads to major alterations in the metabolic activity of neuronal cells which dramatically impair dopaminergic function in vivo. These results highlight the central role of PGC-1α in the function and survival of dopaminergic neurons and the critical need for maintaining physiological levels of PGC-1α activity.

Show MeSH
Related in: MedlinePlus