PPARγ and PGC-1α as Therapeutic Targets in Parkinson’s
Juan Carlos Corona
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Michael R. Duchen
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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.
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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)