Browsing by Subject "Disease Models, Animal"

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  • Hytönen, Marjo K.; Lohi, Hannes (2016)
  • Mäkelä, Johanna (2016)
    Neurodegenerative diseases are characterized by the progressive loss of structure and function of neurons, but the underlying mechanisms for this are largely unknown. Disturbed cell signaling and protein metabolism as well as mitochondrial dysfunctions are thought to be involved in several neurodegenerative diseases. Mitochondria are the major source of energy in the cell, and they also regulate cell death. In brain, neurons are highly dependent on oxidative energy metabolism. Mitochondrial dysfunctions cause oxidative stress with an excess production of reactive oxygen species (ROS). In neurodegenerative diseases such as Parkinson s disease (PD), ROS are thought to contribute to the loss of dopaminergic neurons in substantia nigra pars compacta (SNpc), which leads to dopamine depletion in striatum. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a transcriptional co-activator that regulates mitochondrial biogenesis, ROS defense and respiration. The lack of PGC-1α has been shown to increase the sensitivity of neurons to oxidative stress and brain injuries. In this study we show that increasing the expression of PGC-1α protects against toxin-induced oxidative stress in dopaminergic neurons. We show that PGC-1α expression in dopaminergic neurons can be modulated by resveratrol (RSV), fibroblast growth factor 21 (FGF21) and peroxisome proliferator- activated receptor γ (PPARγ) that are known to regulate metabolism in other tissues. The increase in PGC-1α expression and activation was linked to metabolic changes mimicing low energy levels in the cell, and an increase in SIRT1, a metabolic regulator sensing changes in energy levels. PGC-1α activation was further associated with an increase in mitochondrial respiration and antioxidant levels suggesting that the neuroprotective effect of PGC-1α was due to an improved capacity to combat oxidative stress. These results show that regulation of metabolism by PGC-1α activators could be a useful tool to prevent neurodegeneration in PD. In addition to modulating PGC-1α, RSV was also found to increase the expression of dopamine transporter (DAT) in dopaminergic neurons of female mice. The increase in the level of DAT increases the uptake of dopamine, further indicating that RSV has beneficial effects in dopaminergic neurons. By affecting DAT, RSV also contributes to maintaining functional neurons, as a decline in DAT has been associated with degeneration of dopaminergic neurons. This effect on DAT expression was mediated by estrogen receptors, indicating that the effect of RSV differs between genders that should be considered if RSV is used as therapy for patients with PD.