Neuroprotective effects of PGC-1α activators in dopaminergic neurons

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http://urn.fi/URN:ISBN:978-951-51-2084-7
Title: Neuroprotective effects of PGC-1α activators in dopaminergic neurons
Author: Mäkelä, Johanna
Contributor: University of Helsinki, Faculty of Medicine, Institute of Biomedicine, Department of Biochemistry and Developmental Biology
Minerva Foundation Institute for Medical Research
Thesis level: Doctoral dissertation (article-based)
Belongs to series: Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis - URN:ISSN:2342-317X
Abstract: 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.Parkinsons sjukdom är en neurodegenerativ sjukdom som karakteriseras av en progressiv degenerering av både struktur och funktion hos dopaminerga neuron. En förlust av dopaminerga neuron i mitthjärnan leder till brist på signalsubstansen dopamin, vilket ger upphov till de typiska symptomen vid Parkinsons sjukdom: stelhet, darrning av armar och ben samt rörelsesvårighet. Den nuvarande behandlingen av Parkinsons sjukdom fokuserar på att lindra symptomen, men det finns inte för tillfället någon behandling som kunde förhindra nervcellsdegenereringen. Mitokondrierna producerar energi i cellerna och nervceller är beroende av en hög produktion av energi. En nedsatt mitokondriefunktion och en ökad oxidativ stress, det vill säga ett tillstånd med en ökad produktion av mycket reaktiva molekyler som kallas fria syreradikaler, anses vara en bidragande orsak till uppkomsten av Parkinsons sjukdom. I denna studie behandlades dopaminerga nervceller med substanser som har visats påverka ämnesomsättningen och mitokondriernas funktion i fettvävnad och muskel. Resultaten visade att behandlingen medförde en förbättrad mitokondriefunktion och ett ökat uttryck av antioxidanter som medför en ökas förmåga att motstå oxidativ stress. Nervcellerna var också mera resistenta mot toxin-inducerad celldöd, vilket antas vara på grund av den ökade förmågan att motstå oxidativ stress. Dessa resultat kan vara av betydelse för att förhindra att dopaminerga neuron förtvinar, och substanser som nu används för behandling av metaboliska förändringar skulle kunna vara av betydelse även vid behandling av Parkinsons sjukdom.
URI: URN:ISBN:978-951-51-2084-7
http://hdl.handle.net/10138/161361
Date: 2016-05-20
Subject: biomedicin
Rights: This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.


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