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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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Co-injection of AAV-aSyn and AAV-PGC-1α vectors induces expression of PGC-1α and aSyn in nigral neurons. Immunostaining shows the co-expression of PGC-1α and aSyn in TH-positive neurons in the SNpc of PGC1α-KO mice, at 6 months post-AAV injection. Scale bar: 20 μm.
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Fig7: Co-injection of AAV-aSyn and AAV-PGC-1α vectors induces expression of PGC-1α and aSyn in nigral neurons. Immunostaining shows the co-expression of PGC-1α and aSyn in TH-positive neurons in the SNpc of PGC1α-KO mice, at 6 months post-AAV injection. Scale bar: 20 μm.

Mentions: The significant protective effect observed with the AAV-PGC-1α vector prompted further investigation to determine if the same vector could prevent neuronal degeneration in vivo. To address this question, we assessed if injection of the AAV-PGC-1α vector in the SNpc of PGC1α-KO mice could protect nigral neurons against aSyn toxicity. As intranigral injection of the AAV-aSyn vector produced only mild neurodegenerative effects in our previous experiment, we used another vector design including an optimized kozak sequence and the WPRE enhancer element to increase the rate of aSyn translation. In a previous study, this vector was found to express higher levels of aSyn in the rat SNpc [26]. We first assessed if the co-expression of aSyn and PGC-1α could be achieved on the long-term following co-injection of the two vector suspensions. Indeed, we could detect by immunohistochemistry a clear overexpression of both mouse PGC-1α and human aSyn in a significant proportion of TH-labeled dopaminergic neurons, 6 months post-injection of the vector mix (Figure 7).Figure 7


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)

Co-injection of AAV-aSyn and AAV-PGC-1α vectors induces expression of PGC-1α and aSyn in nigral neurons. Immunostaining shows the co-expression of PGC-1α and aSyn in TH-positive neurons in the SNpc of PGC1α-KO mice, at 6 months post-AAV injection. Scale bar: 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4379693&req=5

Fig7: Co-injection of AAV-aSyn and AAV-PGC-1α vectors induces expression of PGC-1α and aSyn in nigral neurons. Immunostaining shows the co-expression of PGC-1α and aSyn in TH-positive neurons in the SNpc of PGC1α-KO mice, at 6 months post-AAV injection. Scale bar: 20 μm.
Mentions: The significant protective effect observed with the AAV-PGC-1α vector prompted further investigation to determine if the same vector could prevent neuronal degeneration in vivo. To address this question, we assessed if injection of the AAV-PGC-1α vector in the SNpc of PGC1α-KO mice could protect nigral neurons against aSyn toxicity. As intranigral injection of the AAV-aSyn vector produced only mild neurodegenerative effects in our previous experiment, we used another vector design including an optimized kozak sequence and the WPRE enhancer element to increase the rate of aSyn translation. In a previous study, this vector was found to express higher levels of aSyn in the rat SNpc [26]. We first assessed if the co-expression of aSyn and PGC-1α could be achieved on the long-term following co-injection of the two vector suspensions. Indeed, we could detect by immunohistochemistry a clear overexpression of both mouse PGC-1α and human aSyn in a significant proportion of TH-labeled dopaminergic neurons, 6 months post-injection of the vector mix (Figure 7).Figure 7

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