Parkin functionally interacts with PGC-1 proportional to to preserve mitochondria and protect dopaminergic neurons

To understand the cause of Parkinson's disease (PD), it is important to determine the functional interactions between factors linked to the disease. Parkin is associated with autosomal recessive early-onset PD, and controls the transcription of PGC-1a, a master regulator of mitochondrial biogenesis. These two factors functionally interact to regulate the turnover and quality of mitochondria, by increasing both mitophagic activity and mitochondria biogenesis. In cortical neurons, co- expressing PGC-1a and Parkin increases the number of mitochondria, enhances maximal respiration, and accelerates the recovery of the mitochondrial membrane potential following mitochondrial uncoupling. PGC-1a enhances Mfn2 transcription, but also leads to increased degradation of the Mfn2 protein, a key ubiquitylation target of Parkin on mitochondria. In vivo, Parkin has significant protective effects on the survival and function of nigral dopaminergic neurons in which the chronic expression of PGC1a is induced. Ultrastructural analysis shows that these two factors together control the density of mitochondria and their interaction with the endoplasmic reticulum. These results highlight the combined effects of Parkin and PGC- 1a in the maintenance of mitochondrial homeostasis in dopaminergic neurons. These two factors synergistically control the quality and function of mitochondria, which is important for the survival of neurons in Parkinson's disease.

The effect of the functional interaction between PGC-1α and Parkin on mitochondrial quality control in Parkinson's disease

Lu Zheng

Although several genetic factors have been directly associated to Parkinsonâs disease (PD), no single pathway has emerged to explain the etiology of this neurodegenerative disease. To further understand the cause of Parkinsonâs disease (PD), it is therefore important to deter-mine if and which functional interactions exist between gene products linked to this complex brain disorder. Mutations in the gene encoding the E3 ubiquitin ligase Parkin are associated to autosomal recessive PD with early onset. Although the Parkin protein carries out various critical func-tions in the cell, its role in mitochondria quality control, by inducing the autophagic degrada-tion of damaged mitochondria, has attracted a lot of attention. Furthermore, Parkin has been found to control the transcription of PGC-1Î±, a master regulator of mitochondrial biogenesis. Based on the important role that mitochondria are considered to play in PD, and the evi-dence for the coordinated expression of Parkin and PGC-1Î±, we sought to explore in neurons how these two factors functionally interact to regulate mitochondria turnover and quality control. In cortical neuronal cultures, we found that Parkin and PGC-1Î± have synergistic effects on mitochondrial biogenesis, and that the co-expression of these two factors leads to a dramatic increase in the number of mitochondria per cell. We further explored the effects of these fac-tors on the mitochondrial function. Parkin was shown to enhance the maximal respiration rate of neurons exposed to a mitochondrial uncoupling agent only in the presence of PGC-1Î±. Consistent with this effect, the co-expression of Parkin and PGC-1Î± leads to rapid recovery of the mitochondrial membrane potential following mitochondrial uncoupling. Next, we explored the molecular changes, which may underlie the cooperation between Par-kin and PGC-1Î±. The expression of Tfam, an important mitochondrial transcription factor, was found to be controlled synergistically by these two factors. Furthermore, PGC-1Î± en-hances the turnover of Mfn2, a key ubiquitylation target of Parkin. This result suggests that part of the functional interaction between PGC-1Î± and Parkin may be mediated via the co-regulation of Mfn2, a critical factor in mitochondrial physiology which controls the dynamics of mitochondria as well as their association with the endoplasmic reticulum (ER). In the rat substantia nigra, Parkin activity has significant protective effects on the survival and function of nigral dopaminergic neurons in which the chronic expression of PGC-1Î± is in-duced. Ultrastructural analysis shows that the conjunction of these two factors controls the density of mitochondria and their interaction with the ER. In PGC-1Î±-expressing dopamin-ergic neurons, the co-expression of mutated variants of Parkin associated with familial PD leads to accelerated degeneration. Overall, this study shows that Parkin, in conjunction with the transcription co-regulator PGC-1Î±, may play an important role in modulating the biogenesis of mitochondria as well as the quality control of this organelle. In nigral dopaminergic neurons which may critically depend on the mitochondria for their function and survival, the functional interaction be-tween these two factors should be further explored in the context of PD.

EPFL2016

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

Patrick Aebischer, Julien Dusonchet, Sylvain Eric Lengacher, Bernard Schneider

Mitochondrial dysfunction and oxidative stress have been implicated in the etiology of Parkinsons 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-1), a transcriptional regulator of mitochondrial function, both in vitro and in vivo. In neuronal primary cultures from the ventral midbrain, PGC-1 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-1 progressively leads to a decrease in mitochondrial polarization. In the adult rat nigrostriatal system, adeno-associated virus (AAV)-mediated overexpression of PGC-1 induces the selective loss of dopaminergic markers and increases dopamine (DA) catabolism, leading to a reduction in striatal DA content. In addition, PGC-1 prevents the labeling of nigral neurons following striatal injection of the fluorogold retrograde tracer. When PGC-1 is expressed at higher levels following intranigral AAV injection, it leads to overt degeneration of dopaminergic neurons. Finally, PGC-1 overexpression does not prevent nigrostriatal degeneration in pathologic conditions induced by -synuclein overexpression. Overall, we find that lasting overexpression of PGC-1 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-1 in the function and survival of dopaminergic neurons and the critical need for maintaining physiological levels of PGC-1 activity.

Oxford University Press2012

The effect of the functional interaction between PGC-1α and Parkin on mitochondrial quality control in Parkinson's disease

Lu Zheng

EPFL2016

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

Patrick Aebischer, Julien Dusonchet, Sylvain Eric Lengacher, Bernard Schneider

Oxford University Press2012