PPARs and Their Neuroprotective Effects in Parkinson’s Disease: Comparison
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Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Luis O. Soto-Rojas.

Peroxisome proliferator-activated receptor (PPARs) belong to subgroup 1 of the nuclear receptor superfamily. They are known to form heterodimers with the RXR when activated by endogenous or exogenous ligands and to bind to a co-activator such as PGC-1α.

  • α-synucleinopathy
  • neuroprotection
  • Parkinson’s disease
  • PPARs
  • neuroregeneration

1. Peroxisome Proliferator-Activated Receptor (PPARs): Types, Distribution and Functions

PPARs belong to subgroup 1 of the nuclear receptor superfamily [51][1]. They are known to form heterodimers with the RXR when activated by endogenous or exogenous ligands and to bind to a co-activator such as PGC-1α. The activated PPAR complex binds to peroxisomal proliferative-response elements (PPREs), promoting gene transcription. Three isoforms of these receptors are known as the α, γ, and β/δ isoforms. However, the PPARγ gene generates three transcripts by alternative splicing encoding for further γ isoforms [52][2], which are involved in lipid metabolism, mitochondrial biogenesis, cellular energy production, glucose and amino acid regulation, and thermogenesis [53][3]. Also, PPARs are activated by lipids consumed in the diet (fatty acids) or their metabolites (such as eicosanoids), and they are considered to be lipid sensors [54][4].
PPARs are ubiquitously expressed in the organism, as shown in Table 1, while the β/δ isoform is mainly expressed in the CNS, however, the γ isoform is the most studied therapeutic target in several neurodegenerative diseases [55][5]. According to data retrieved from the Genotype-Tissue Expression (GTEx) project, the region with the most abundant expression is the caudate nucleus for α isoform, the cerebellar hemisphere for γ, and the cerebellum for β/δ. In addition, several nuclei from the basal ganglia are included, including the same ones that play an essential role in the motor deterioration of diseases such as PD and Huntington’s disease (HD). On the other hand, Table 1 highlights the agonists corresponding to each isoform. It is worth mentioning that fatty acids and their derivatives could activate all isoforms and are considered pan-agonists or/and endogenous agonists. According to some research groups, there is a connection between the three isoforms called “the PPARs triad”. Activation of the triad regulates neuroprotection by promoting PPAR-dependent genes, including positive feedback on PPARs themselves [56][6]. PPARγ increases the levels of the β/δ isoform, and vice versa, PPARβ/δ increases PPARγ levels. In addition, the β/δ isoform regulates α and γ activation, inducing the production of their endogenous agonists [57][7]. According to the PPAR triad theory, PPARγ is essential for triad maintenance even in regions of the CNS where the abundance of the β/δ isoform predominates.
Table 1 shows the ligands for PPAR divided into endogenous and exogenous, but these ligands can also act as selective agonists for one isoform, agonists with dual effect, or pan-agonists. The neuroprotection that agonists can provide depending on their mode of action is discussed in what follows.
Several animal models of PD, HD, and Alzheimer’s disease (AD) have shown a neuroprotective effect of PPARγ activation by agonists [55,58,59][5][8][9]. Glitazones (rosiglitazone, pioglitazone, and lobeglitazone) are the most widely studied PPARγ ligands, indicating the importance of this isoform [60][10]. The main effects of specific PPARγ activation include prevention of mitochondrial dysfunction, reduction of ROS, LP production, increased PGC-1α production, suppression of autophagy, maintenance of mitochondrial membrane potential (ΔΨm), inhibition of the proinflammatory cytokines, preservation of dopaminergic neurons, and reduction of macrophage infiltration [61,62,63,64,65][11][12][13][14][15].
On the other hand, recent studies point to the PPARα isoform being the target for preventing damage in AD, PD, depression, and schizophrenia [66,67,68][16][17][18]. Fibrates (fenofibrate, clofibrate) are the main agonists of the α isoform, and recent studies have shown a neuroprotective effect, especially in the case of gemfibrozil [69,70][19][20]. The different neuroprotective mechanisms related to PPARα activation are: (a) maintenance of glutamate homeostasis; (b) regulation in the metabolism of amyloid beta (Aβ) peptide; (c) cholinergic/dopaminergic signaling in the CNS; (d) attenuation of behavioral changes and dopaminergic dysfunction; (e) antidepressant activity; and (f) decreased proinflammatory signals and astrogliosis [66,67,71,72][16][17][21][22].
Regarding the β/δ isoform, some specific agonists known are L-165041, GW0742, and KD3010; the last one reported as safe in the Phase 1b Clinical Trial for metabolic disorders treatment, including obesity [73,74,75][23][24][25]. Activation of the β/δ PPAR isoform resulted in neuronal protection in various brain pathologies, such as cerebral ischemia, multiple sclerosis, amyotrophic lateral sclerosis, HD, PD, and AD [74,76,77,78,79,80,81][24][26][27][28][29][30][31]. In addition, neuroprotective effects conferred by PPAR β/δ activation include the regulation of ceramide metabolism, the reduction of (Aβ) aggregates, anti-inflammatory and antiapoptotic activity, prevention in mitochondrial dysfunction, decreased neutrophil infiltration, diminished oxidative stress and synthesis of antioxidant enzymes, ultimately leading to the restoration of cognitive functions [74,75,77,78,82][24][25][27][28][32].
Some ligands also exhibit dual effects, for example, 4-hydroxynonenal (4-HNE)-mediated PPAR β/δ antagonist/PPAR γ agonist has been verified to counteract the primary and secondary signs of PD neurodegeneration [83][33]. In addition, MHY908, a PPAR α/γ dual agonist, prevents the loss of dopaminergic neurons and motor deficits in a PD model [84][34].
Finally, the known endogenous agonists are considered to be pan-agonists. Belonging to these ligands are some fatty acids. However, agonists of similar lipidic nature that are exogenous is also found (consumed by the diet; see Table 1), as in the case of exogenous fatty acids (oleic acid, eicosapentaenoic acid, and docosahexaenoic acid) that promote PPARγ receptor expression [85][35]. Also, synthetic pan agonists (GFT1803 and bezafibrate) have been reported to prevent brain glucose hypometabolism and neuronal loss, attenuate microgliosis and the development of behavioral features in models of AD and Tau pathology [86,87][36][37].
Table 1.
Expression of PPARs in the brain and their neuroprotective effects.
Receptor Isoform/Agonist Brain Expression

(TPM *)		 Neuroprotection Effects Ref.
PPAR-α

Endogenous: Fatty acids such as palmitic, stearic, palmitoleic, oleic, linoleic, AA and EPA.

Exogenous: WY-14643, clofibrate, gemfibrozil, nafenopin, bezafibrate, and fenofibrate.		 Cd (4.799), Sc (4.660), SN (4.562), Acc (4.402), Acb (4.398), Cx (4.241) Amg (4.204), Pu (3.801), FroCx (3.677), Hy (3.597), Cb (3.561), HiF (3.057), CbH (2.399). Participates in neurotransmission processes, decreases neuroinflammation, oxidative stress, and Aβ aggregation. [59,88][9][38]
PPAR-β/δ

Endogenous: EPA, linoleic acid, 13-S-HODE, and 4-HNE.

Exogenous: WY-14643, GW0742, GW501516, KD3010, and L-165041.		 Cb (46.72), CbH (42.24), Cx (36.76), FroCx (34.37), HiF(27.25), Sc (26.71), Acc (26.45), SN (22.51), Hy (21.20), Acb (20.36), Cd (20.27), Pu (18.38), Amg (2.77). Prevents damage in neurodegeneration (AD, PD, HD, MS, and ALS) ischemia, CNS traumatic injury, and neuroinflammation. [74,79,80,81,83,89][24][29][30][31][33][39]
PPAR-γ

Endogenous: AA, EPA, and 15 deoxy PGJ12.

Exogenous: Pioglitazone, Rosiglitazone Ibuprofen, piroxicam, ciglitazone, and GW1929.		 CbH (2.744), Cb (2.425), FroCx (2.175), Acc (1.835), Cx (1.834), Acb (1.546), Sc (1.473), HiF (1.344), Amg (1.268), Hy (1.058), Cd (0.9625), SN (0.8271), Pu (0.7124).
Abbreviations: Acb, nucleus accumbens; Acc, anterior cingulate cortex; AD, Alzheimer’s disease; ALS, Amyotrophic lateral sclerosis; Amg, amygdala; AA, arachidonic acid; Cb, cerebellum; Aβ, amyloid beta; CbH, Cerebellar Hemisphere; Cd, caudate nucleus; CNS, central nervous system; Cx, cortex; EPA, eicosapentaenoic acid; FroCx, frontal cortex; HD, Huntington’s disease; HiF, hippocampal formation; Hy, hypothalamus; MS, multiple sclerosis; PD, Parkinson’s disease; PG, pituitary gland; Pu, putamen; Sc, spinal cord (cervical c-1), SN, substantia nigra; TPM: transcripts per million; 15 deoxy PGJ12, 15 deoxy PGJ2, 15-Deoxy- ∆-12,14-Prostaglandin J2; 13-S-HODE, 13-S-hydroxyoctadecadienoic acid; 4-HNE, 4-hydroxynonenal; * Data Source: GTEx Analysis Release V8 (dbGaP Accession phs000424.v8.p2).

2. Effects of PPARs Agonists on Other Neurodegenerative Disorders

Nowadays, PPAR agonists are considered effective in various neurodegenerative diseases such as PD, AD, and HD. Interestingly, AD and PD share several pathological features, including increased incidence with age, chronic and progressive neuronal death, neuroinflammation, mitochondrial dysfunction from elevated ROS production, and protein misfolding [128,129,130][40][41][42]. However, specifically in AD brains, two pathognomonic features are observed mainly in the hippocampus [131,132][43][44]: (1) extracellular deposits of amyloid beta peptide (Aβ); and (2) intracellular aggregates of pathological tau protein. Recently, it has been postulated that endogenous “damage signals” such as Aβ oligomers or ROS, could cause microglial activation followed by the release of proinflammatory cytokines that trigger Tau hyperphosphorylation and aggregation, and when neurons die, Tau is released and causes microglial activation, generating a vicious circle that leads to neurodegeneration [133][45]. Unfortunately, most of the current therapeutic approaches have not been successful, since they focus on isolated, partial mechanisms of the overall pathology [134,135][46][47]. Therefore, the treatment of neurodegenerative diseases should be considered in light of the multiconvergent theory [136,137][48][49] in the face of various neuropathological events such as neuroinflammation, oxidative stress, and protein misfolding. In this context, PPAR analogs would be useful for the treatment of these neurodegenerative disorders [138,139,140,141,142][50][51][52][53][54]. For example, PPARγ agonists have been reported to modulate the expression of various AD-related genes, such as Bcl-2, which is involved in hippocampal neurodegeneration [143][55], and they have also been shown to reduce Aβ peptide levels both by increasing its clearance and by modifying the activity of secretases that are involved in its metabolism [144,145][56][57]. Likewise, it has been suggested that PPARs play a key role in the regulation of oxidative stress and neuroinflammation [140][52]. On the other hand, HD is a neurodegenerative disorder that affects movement and similar neuroanatomical structures as in PD. However, HD is characterized by the presence of involuntary choreatic movements, neuropsychiatric symptoms, and cognitive impairment [146,147][58][59]. It originates from a mutation in the huntingtin gene (HTT), which specifically causes aggregation of the huntingtin protein in the cortex and caudate/putamen [138][50]. Mitochondrial dysfunction is also related to the development of HD pathogenesis, and PPAR alteration plays an important role [76,148][26][60]. It has been found that overexpression of PGC-1α improves the motor phenotype, decreases neurodegeneration and the accumulation of the mutant huntingtin protein, by attenuating oxidative stress [149][61]. Likewise, activation of PPARδ and PPARγ by their agonists, KD3010 and rosiglitazone, respectively, increases survival, normalizes endoplasmic reticulum stress, reduces huntingtin aggregates, and improves mitochondrial function [76,150][26][62]. Therefore, these findings support the use of PPARs as a therapeutic strategy in neurodegenerative diseases. Finally, a close association between neurodegenerative diseases and diabetes mellitus (DM) has been described [151,152][63][64]. DM constitutes a great global health challenge for around 460 million people worldwide [153][65]. According to preclinical assays, possible neuropathological mechanisms involved in these pathologies have been postulated [154,155][66][67]: (i) cerebrovascular disease; (ii) misfolding of proteins; (iii) chronic insulin resistance, which is associated with PGC-1α downregulation, mitochondrial complex I dysfunction, neuroinflammation, and impaired autophagy; (iv) amylin neuropathology. Amylin, a highly amyloidogenic pancreatic peptide, is increased in DM patients, can cross the BBB and accelerate α-syn [156][68] aggregation, Tau [157][69] phosphorylation, and Aβ [158][70] aggregates. Although DM patients treated with PPAR agonists have a lower risk of developing neurodegenerative disorders [159,160][71][72], evidence correlating PPAR dysfunction is lacking.

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