PPARγ and PGC-1α as Therapeutic Targets in Parkinson’s

Neurochemical Research, Jul 2014

The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcriptional factor that belongs to the nuclear hormone receptor superfamily. PPARγ was initially identified through its role in the regulation of glucose and lipid metabolism and cell differentiation. It also influences the expression or activity of a number of genes in a variety of signalling networks. These include regulation of redox balance, fatty acid oxidation, immune responses and mitochondrial function. Recent studies suggest that the PPARγ agonists may serve as good candidates for the treatment of several neurodegenerative disorders including Parkinson’s disease (PD), Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis, even though multiple etiological factors contribute to the development of these disorders. Recent reports have also signposted a role for PPARγ coactivator-1α (PGC-1α) in several neurodegenerative disorders including PD. In this review, we explore the current knowledge of mechanisms underlying the beneficial effects of PPARγ agonists and PGC-1α in models of PD.

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PPARγ and PGC-1α as Therapeutic Targets in Parkinson’s

Juan Carlos Corona 0 Michael R. Duchen 0 0 J. C. Corona M. R. Duchen (&) Department of Cell and Developmental Biology, University College London , London WC1E 6BT, UK The peroxisome proliferator-activated receptor gamma (PPARc) is a ligand-activated transcriptional factor that belongs to the nuclear hormone receptor superfamily. PPARc was initially identified through its role in the regulation of glucose and lipid metabolism and cell differentiation. It also influences the expression or activity of a number of genes in a variety of signalling networks. These include regulation of redox balance, fatty acid oxidation, immune responses and mitochondrial function. Recent studies suggest that the PPARc agonists may serve as good candidates for the treatment of several neurodegenerative disorders including Parkinson's disease (PD), Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis, even though multiple etiological factors contribute to the development of these disorders. Recent reports have also signposted a role for PPARc coactivator1a (PGC-1a) in several neurodegenerative disorders including PD. In this review, we explore the current knowledge of mechanisms underlying the beneficial effects of PPARc agonists and PGC-1a in models of PD. - The peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors that belong to the hormone nuclear receptor superfamily. They are involved in the transcriptional control of genes regulating various physiological processes such as lipid homeostasis, glucose metabolism, inflammation, cellular differentiation and proliferation [1, 2]. PPARs act mainly as lipid sensors, regulating metabolism in response to dietary lipid intake and direct the subsequent metabolism and storage of lipids [3]. Three isoforms have been identified, PPARa, PPARb/ d, and PPARc. These three isoforms differ in terms of their tissue distribution, ligand specificity and physiological role. PPARa acts primarily to regulate energy homeostasis through its ability to stimulate the breakdown of fatty acids and cholesterol, driving gluconeogenesis and reduced triglyceride levels. This receptor in particular acts as a lipid sensor, binding fatty acids and initiating their subsequent metabolism. The PPARb/d receptors bind and respond to VLDL-derived fatty acids, eicosanoids, including prostaglandin A1, and are involved in fatty acid oxidation. PPARc stimulates adipocyte differentiation and lipid metabolism. PPARc operates in the metabolism of lipid and carbohydrate metabolism and its activation is related to reduction of glucose levels [4]. Peroxisome proliferator-activated receptors (PPARs) are activated by small, lipophilic compounds and regulate gene expression by forming heterodimers with retinoid-Xreceptors. Once activated the PPAR/retinoid-X-receptors heterodimer binds to the specific DNA sequence [peroxisome proliferator response element (PPRE)] on the promoter region of PPAR target genes [2, 5] to modulate transcriptional activity. The activity of PPARs is also regulated by posttranslational modification such as phosphorylation and sumoylation [6, 7]. For example, there are several mechanisms involved in PPARc inactivation. Thus, phosphorylation can negatively or positively affect PPARc activity depending on which specific protein residue is modified [811]. The PPARc activity is decreased via the ubiquitination degradation pathway [12]. Alternatively, PPARc sumoylation promotes the repression of inflammatory or adipocyte differentiation genes [6, 13]. Peroxisome proliferator-activated receptor alpha (PPARa) ligands include fibrates that are commonly used for the treatment of hypertriglyceridemia and WY14,643 and GW7647. PPARb/d ligands include the prostacyclin PGI2, and synthetic compounds GW0742, GW501516, and GW7842. All PPARs can be activated by polyunsaturated fatty acids with different affinities [14, 15]. Naturally occurring PPARc ligands include long chain fatty acids, other natural lipid ligands, eicosanoids and the prostaglandin 15d-PGJ2, but also few nonsteroidal antiinflammatory drugs, as ibuprofen, fenoprofen, and indomethacin A [1517]. Synthetic thiazolidinediones (TZDs), including pioglitazone and rosiglitazone were originally designed as PPARc agonists and are currently in clinical use as insulinsensitizing agents for the treatment of type 2 diabetes [15, 18]. Distribution of PPARs Peroxisome proliferator-activated receptor alpha (PPARa) is highly expressed in metabolically active tissues, such as liver, kidney, intestine, heart, skeletal muscle, adrenal gland and pancreas during foetal development of rodents [19, 20]. In adult rodent organs, the distribution of PPARa is similar to its foetal pattern of expression. In the central nervous system (CNS), PPARa is expressed at very low levels predominantly in astrocytes and PPARa is most highly expressed in tissues that catabolise fatty acids, such as the adult liver, heart, kidney, (...truncated)


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Juan Carlos Corona, Michael R. Duchen. PPARγ and PGC-1α as Therapeutic Targets in Parkinson’s, Neurochemical Research, 2014, pp. 308-316, Volume 40, Issue 2, DOI: 10.1007/s11064-014-1377-0