Estrogen Related Receptor Alpha: Potential Modulator of Age-Related Macular Degeneration

Abstract

To develop effective therapies for complex blinding diseases such as age-related macular degeneration (AMD), identification of mechanisms involved in its initiation and progression is needed. The estrogen related receptor alpha (ESRRA) is an orphan nuclear receptor that regulates several AMD-associated pathogenic pathways. However, it has not been investigated in detail in the ocular posterior pole during aging or in AMD. This review delves into the literature highlighting the significance of ESRRA as a molecular target that may be important in the pathobiology of AMD and data available supporting targeting this receptor signaling pathway as a therapeutic option for AMD.

1. Introduction

Age-related macular degeneration (AMD) is a neurodegenerative blinding disease affecting the elderly. The lack of treatments able to improve vision or reverse vision loss in these patients is in part due to its multi-factorial nature, in which there is no clear causative culprit. Many of the treatments under consideration aim to target genes reported as risk factors, with marginal success, pointing to a need to think outside the box and identify other regulators of cellular homeostasis altered during aging and disease development. Here in we discuss the known functions of an orphan nuclear receptor called estrogen related receptor alpha (ESRRA) in neurodegenerative diseases that share common pathogenic pathways with AMD and discuss its potential role in AMD development and as a drug target.

2. Age Related Macular Degeneration

Age-Related Macular Degeneration (AMD) is the principal cause of central visual loss among industrialized nations in the western hemisphere. An estimated 10 million Americans are afflicted with AMD, which is comparable in scope to the 12 million Americans living with cancer or the 5 million living with Alzheimer’s disease [1]. Furthermore, due to the demographic transition and growing aging population, the prevalence and burdens of AMD are projected to continue to rise. Treatment of AMD is largely an unmet need. The limited Food and Drug Administration (FDA) approved therapies are targeted to the end-stages of the disease and effective in only a sub-set of patients. Additionally, these clinic-based treatments are available at high-cost and high-effort for the patient [1,2].

2.1. Risk Factors

AMD is a complex disease with multiple risk factors implicated in its development and progression, compounding the difficulty in identifying successful therapies. While the most asserted risk factor for AMD is advanced age, the main modifiable risk factor for AMD is smoking [3]. Other factors such as UV exposure, female gender, increased body mass index (BMI), white race, and education are less often associated but notable [4]. Additionally, epidemiological, and genetic based studies have indicated a defining role for multiple genetic factors, complement pathways, oxidative stress, immune dysregulation, disrupted clearance mechanisms and altered lipid metabolism, to name a few, in the etiology of AMD [5].

2.2. AMD Clinical Subtypes and Pathogenesis

There are two broadly described presentations of AMD – the “wet” and “dry” forms (Table 1). The dry form, which itself can further be classified as “early” and “late”, is the most common presentation of AMD [6]. Late dry AMD, also known as geographic atrophy (GA) occurs during the later stages of the disease and is characterized by significant retinal pigment epithelial (RPE) degeneration, while the early dry form is noted by the accumulation of yellow appearing deposits composed of lipids and proteins that build up between the RPE and Bruch’s membrane, called drusen [6]. The exact mechanism of how drusen lead to RPE dysfunction and subsequent photoreceptor death is not fully understood, but it is thought to involve inflammation, oxidative stress, and impaired waste removal [6,7]. Importantly, functional, and biological changes in RPE with age have been proposed as initiating factors for disease development. These changes include high metabolic activity of the macula over an individual’s lifetime, which places significant demand on the RPE, the main support cell layer to the overlying retina, for the breakdown and removal of metabolic waste products, accumulation of lipofuscin, a pigment that accumulates in RPE cells as a result of normal aging, which itself is subject to oxidative stress, potentially affecting lysosomal function, thus contributing to disease development [4–6]. The wet form of AMD, also known as exudative or neovascular, is characterized by the growth of abnormal blood vessels from the choroid, below the RPE and within the macula. These blood vessels leak fluid and blood, leading to scarring and damage to the RPE, photoreceptor cells, and the overlying retina. The exact trigger for the growth of these blood vessels is not fully understood, but it is thought to involve inflammation, oxidative stress, and several angiogenic factors, including vascular endothelial growth factor (VEGF) [2,8].

Table 1.

Brief overview of AMD, risk factors, and clinical subtype pathogenesis.

What is AMD?	Stage	Prevalence in the United States by Age	Phenotype	Presentation	Select Risk Factors
The principal cause of central visual loss in the western hemisphere. In AMD, a part of the retina called the macula is damaged. An estimated 10 million Americans are afflicted with AMD. The prevalence and burden of AMD are projected to continue to rise.	Early Stage AMD	40–49: 3.71% 50–59: 8.75% 60–69: 12.44% 70–79: 20.98% 80–89: 30.23% 90–99: 55.83%	Dry AMD: • Drusen • RPE dysfunction • RPF thinning • Photoreceptor degeneration • Inflammation		• Increasing age • Smoking • Family history • White race • Female sex
	Late Stage AMD	40–49: 0.05% 50–59: 0.16% 60–69: 0.32% 70–79: 1.16% 80–89: 6.91% 90–99: 15.98%	Geographic atrophy: • Loss/atrophy of RPE • Photoreceptor cell death • Evolution of drusen into atrophic areas • Inflammation		• GA is an advanced form of dry AMD and shares many risk factors with early dry AMD
			Wet, neovascular, or exudative AMD • Emerges abruptly • Hemorrhage • Choroidal neovascularization • Fluid accumulation		• Family history • Cardiac health • Smoking • White race • Female sex

2.3. Therapeutic Candidates

Anti-VEGF therapy such as Lucentis (a monoclonal antibody fragment) and Aflibercept (a decoy receptor), have become the standard treatment for neovascular, or wet AMD [2]. These drugs work by blocking Vascular Endothelial Growth Factor (VEGF), a potent signaling protein, critical to the angiogenic pathway, thus hindering the formation and progression of etiological permeable blood vessels from the choroid [9]. Though these treatments have reduced the blinding rate for patients, approximately 30% of patients are non - responsive to treatment and/or cannot maintain their vision following long-term treatment [9]. A further limitation with this approach is that anti-VEGF therapy must be given intensively and repeatedly over a long period of time to alleviate the effects of neovascularization, which fosters the risk of complications and adds to the economic burden experienced by patients [10]. Excitingly, two new treatments for GA have recently been approved by the FDA. Pegcetacoplan, an injectable treatment, is the first medication to use targeted complement C3 therapy to diffuse the harmful “complement cascade” that is triggered by GA, a physiological response that attacks and destroys healthy tissue [11]. In a recent study evaluating Pegcetacoplan’s efficacy in reducing the effects of atrophic AMD, the drug was found to reduce growth by 30% and 20% at month 12 in the monthly and bimonthly treatment groups, respectively [11]. Though a landmark therapy, patients experience zero improvement of symptoms, rather only slowed growth progression of GA. This in part may be because treatment is applied at a stage of significant degeneration, raising the need to consider regenerative therapies. Izervay is a second complement directed medication with FDA approval designed to target complement C5 [12]. Like anti-VEGF therapies, the protocol for these GA drugs requires intense and repetitive injections and patient commitment over the course of months [11,13].

3. Nuclear Receptors as Potential Therapeutic Targets for AMD

Despite extensive research, the critical drivers involved in the initiation of AMD and its progression from the early to advanced stages, remain to be fully understood, challenging the ability to predict progression and, in turn, effective treatments. Breakthroughs in identifying probable pathogenic pathways and molecular mechanisms associated with the disease, however, have been instrumental in the pursuit of generating in vitro and in vivo model systems used as platforms to test potential therapies. These pathways, which are largely related to signaling pathways and mechanisms compromised during aging, include: complement activation, lipid trafficking and metabolism, mitochondrial bioenergetics, lysosomal dysfunction, autophagy/mitophagy dysregulation, choriocapillary drop out, angiogenesis, inflammation, and oxidant induced, and non-oxidant associated cellular injury and stress [6].

Nuclear receptors (NRs), are members of a superfamily of transcription factors, that are emerging as strong therapeutic target candidates [14–16]. Functionally, NRs are key regulators of a myriad of developmental and physiologic pathways, including those aforementioned (e.g., inflammation, lipid metabolism, apoptosis, energy metabolism, and angiogenesis) [14–16]. As such, these pathways are often compromised in retinal diseases such as AMD, indicating that nuclear receptors may be potential regulators of disease. Recent literature has outlined several NRs and receptor regulators that may play a role in retinal cell homeostasis, including peroxisome proliferator activated receptor (PPAR) alpha, beta/delta and gamma, Liver X Receptor (LXR), Retinoid X Receptor Orphan Receptor (ROR), and Nuclear Receptor Related 1 (Nurr1) [15,17–19]. Another nuclear receptor of potential interest is the Estrogen Related Receptor Alpha (ESRRA or ERRa), especially in the realm of AMD, because of its reported role in related neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, as well as systemic diseases such as atherosclerosis [20]. This review serves to outline possible pathways by which ESRRA contributes to AMD pathogenesis and the potential for ESRRA to serve as a pharmacologic target for retinal degeneration.

4. ESRRA Overview

ESRRA is one of three members in the Estrogen Related Receptor (ESRR) family, which belongs to a NR subfamily of orphan receptors called NR3B. This family consists of: ESRRA/NR3B1, ESRRB/NR3B2, ESRRG/NR3B3 [20,21]. The molecular structure of the three ESRRs are quite similar, each composed of conserved regions: an activation function −1 (AF-1) domain, a DNA-binding domain, a ligand-binding domain (LBD), and an AF-2 domain. The main differences lie in the sequence homology of the AF-1 and LBD, with greater homology seen between ESRRB and ESRRG. The term “orphan” indicates that the endogenous ligand of the receptor remains unknown. ESRRA is ubiquitously expressed in nearly all organs to some degree but is most highly expressed in tissues that preferentially utilize fatty acids as energy sources [22,23]. Like other NRs, the functions of ESRRA are tissue and cell specific, ligand dependent, and driven by the presence of co-regulators [21,22]. These receptors regulate target gene transcription through both classical (direct DNA binding) and non-canonical (tethering to other transcription factors) pathways [20–23]. Recent in vitro and in vivo data using hepatic cells and brown adipose tissue presents ESRRA as a regulator of metabolic function and nutrient and energy sensing pathways, involved in cross talk with other tissues, thus establishing the activation of this receptor as an important factor in the development of metabolic disorders [20,22,24]. Other conditions directly and indirectly affected by changes in metabolism and regulated by ESRRA include tumor malignancy, obesity, and degenerative diseases such as Alzheimer’s Disease and osteoporosis [20,22,24].

4.1. ESRRA Activation and Repression Pathways

The primary mechanism integral to the regulation of ESRRA activity is cofactor availability, indicating that the shift between different ESRRA regulated pathways in response to physiologic and metabolic cues is likely driven by distinctive coregulators within the tissue and cellular milieu (Figure 1). Relatedly, ESRRA expression activity is dramatically upregulated by increasing the expression of its most potent coactivator, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in metabolic tissues [21,22]. The expression of PGC1-α serves to coactivate ESRRA forming a feed-forward loop promoting the expression of metabolic genes [21,24,25]. Other potential modifiers of ESRRA expression identified to date, include physiological state specific signals, such as cold exposure, physical exercise, and fasting [24,26,27]. One example is the NR corepressor 1 (NCOR1), a well characterized and ubiquitously expressed corepressor that exerts opposing effects on the transcriptional activity of ESRRA through a histone deacetylase, a core component of the NCOR1 protein [26]. Its binding to the ESRRA ligand binding domain leads to the repression of receptor-mediated transcriptional activity during certain physiological conditions, such as the in-fed state [28]. Receptor-interacting protein or RIP140 is another well-known ESRRA corepressor and has been shown to repress several genes involved in glucose and lipid metabolism in adipocytes and muscle fibers [21,26].

Figure 1:

Overview of ESRRA structure, activation and repression pathways, and impact on physiological processes.

4.2. Discoveries in ESRRA Co-regulation

Recent unbiased statistical expression models of ESRRA-activated genes across various breast cancer cells have identified possible novel co-regulators for ESRRA [29]. The identified ESRRA co-regulators and their cellular functions are quite diverse, including SIRT1 and HDAC8, which join PGC-1α in activating ESRRA [21]. The homeobox protein prospero-related homeobox 1 or PROX1 was identified as a negative modulator of ESRRA/PGC-1α energetic functions in mouse livers [30]. These new models of investigation are exciting, as it is likely that additional transcriptional coregulators of ESRRA remain to be identified and functionally characterized.

5. Molecular Cross-Talk with ESRRA

5.1. HIF-1α with ESRRA

Hypoxia-Inducing Factor 1-α (HIF-1α) is a transcription factor that regulates cellular response to low oxygen levels, or hypoxia, and plays a critical role in cellular adaptation to hypoxia [31]. Recent reports suggest ESRRA and HIF-1α interact with each other to regulate cellular metabolism and response to hypoxia in carcinomic cells [21,31]. Specifically, studies have shown that in certain tissues, ESRRA increases the expression of HIF-1α, which in turn can enhance the activity of ESRRA [32]. This interaction between ESRRA and HIF-1α appears to be important for regulating cellular metabolism under hypoxic conditions and may play a role in the development of certain diseases, such as cancer [32].

5.2. mTOR with ESRRA

mTOR, the mammalian target of rapamycin, is a protein that plays a role in cell growth, proliferation, and survival in part by controlling messenger RNA (mRNA) as a transcriptional regulator of metabolism [33]. Studies show that ESRRA acts downstream of mTOR to promote mitochondrial biogenesis and oxidative metabolism, crucial for energy production in cells. ESRRA is also involved in the regulation of autophagy, a process by which cells break down and recycle cellular components, which is known to be regulated by mTOR [33]. Furthermore, mTOR has been found to modulate ESRRA activity through phosphorylation of specific residues in the receptor, thereby influencing its transcriptional activity [34]. This interaction between mTOR and ESRRA has important implications for a variety of cellular processes, including energy metabolism, cell aging, cell growth, and differentiation [35].

5.3. ESRRA with Other ESRR Isoforms

When present in the same cell, the three ESRR isoforms can form heterodimers though the functional consequence of this interaction is not yet fully understood because ESRRA is not required for ESRRG activity and vice-versa; however, heterodimers have been reported to have lower activity in vitro [20,36]. Furthermore, ESRR isoforms can compensate for each other’s activities as knockdown of two or more ESRR isoforms are required to suppress mitochondrial biogenesis, abrogate the transcriptional response to adrenergic stimulation in brown fat and disrupt normal cardiac bioenergetics [24,26,27]. Nonetheless, gene knockouts in mice have demonstrated that loss of each ESRR isoform results in distinct developmental and tissue-specific phenotypes, demonstrating that each ESRR isoform also has specific roles to play in the control of cellular metabolism, development, regeneration, and environmental adaptation [24,26]. Of note, there is also ample evidence that ESRRA and ESRRG have differential and opposing effects, which may be due to interactions with corepressors, coactivators, post translational modifications, or differential cell expression [26].

5.4. Nur77 with ESRRA

Nur77 (also known as NR4A1), like ESRRA is another transcription factor and orphan nuclear receptor that plays a role in regulating energy metabolism and mitochondrial biogenesis in cells [37]. Studies have shown that Nur77 and ESRRA can interact and form a complex, which activates the expression of genes involved in mitochondrial function, oxidative metabolism, and glucose homeostasis. Nur77’s influence on ESRR activity is by recruiting coactivators or corepressors to the promoter regions of target genes that are regulated by ESRR, resulting in changes in gene expression and ultimately, cellular metabolism [21,37]. Moreover, Nur77 is under investigation as a potential therapeutic target for central nervous system disorders with etiology linked to AMD and ESRRA affected pathways [38].

6. Potential Regulation of AMD Pathogenic Pathways by ESRRA

As mentioned earlier, the complex nature of AMD is reflected in part by the number of pathogenic pathways associated with its development. Previously, we identified the expression of ESRRA in several nuclear receptor atlases of human retinal pigment epithelial cells, human choroidal endothelial cells and the mouse RPE/choroid isolated from a murine model of laser induced choroidal neovascularization, supporting the need to investigate the role of this receptor in ocular health, aging, and disease further [39,40]. As the next step, herein we explore the role of ESRRA in several AMD-relevant pathogenic pathways (Figure 2).

Figure 2.

Potential impact of ESRRA on pathogenic pathways important in AMD development. ESRRA effects lipid metabolism and may promote the translation of Electron Transport Chain (ETC) Complexes I, II, III. Through its interaction with Thyroid Hormone Receptor alpha (TR-ɑ) ESRRA may stimulate production of thyroid hormone (TH)’s target genes to mediate mitochondrial biogenesis. Together, these pathways pave the way for energy production, and when disregulated, may lead to reactive oxygen production. ESRRA can also crosstalk with the Mammalian Target of Rapamycin (mTOR) to regulate autophagy in RPE cells and the production of hypoxia-inducible factor 1 subunit alpha (HIF-1⍺) to modulate inflammation in aging or stressed RPE cells. Finally, ESRRA controls the transcription of vascular endothelial growth factor (VEGF)’s target genes, thus influencing choroidal neovascularization.

6.1. Transcriptional Contributions to Oxidative Stress and Hypoxia

Cellular metabolism, particularly through the electron transfer flavoprotein and increased lipid metabolism, is partially responsible for increasing reactive oxygen species (ROS) production [41]. Remarkably, the first genomic target of ESRRA identified was Acyl-CoA dehydrogenase medium chain (Acadm) which codes for the enzymes that catalyze the first stage of fatty acid oxidation (FAO) [22,26]. Furthermore, ESRRA transcriptionally regulates virtually all mitochondrial actors of ROS production, including genes involved in glycolysis and part of the TCA cycle, complexes I, II, and III of the electron transport chain, and beta-oxidation [21,22,26,31]. Of therapeutic relevance, pharmaceutical inhibition of ESRRA leads to suppression of antioxidant detoxification capacity of breast cancer cells, while inhibition of ESRRA leads to a decrease in intracellular ROS species in insulin resistant hepatocarcinoma, demonstrating the cell and tissue specific qualities of ESRRA [31,41]. Furthermore, ESRRA activation has been shown to promote resistance of prostatic epithelial and cancerous cells to hypoxic conditions by elevating HIF-1α protein levels, leading to facilitated growth in a hypoxic environment [31]. This cooperative behavior between ESRRA and HIF-1α regulates angiogenesis and glycolysis, leading to facilitated growth in a hypoxic environment. Importantly, XCT790, a known inverse agonist of ESRRA, reverses ESRRA-induced resistance to hypoxia, resulting in reduced cell proliferation, clonal formation, and cell invasion capacities [42].

These findings are relevant in the discussion of potential AMD therapies, as hypoxia is thought to be associated with the progression of wet AMD and is linked to elevated cellular lipofuscin, a hallmark of aging in the eye also implicated in several other retinal degenerations. Furthermore, HIF-1α promotes choroidal neovascularization [5,6]. While an aberrant HIF-1α - ESRRA signaling axis has not yet been directly linked to elevated lipofuscin, certainly oxidative stress and mitochondrial dysfunction have been [6,7]. These findings collectively implicate a potential role for ESRRA and HIF-1α to indirectly contribute to the accumulation of lipofuscin pigment through their cross talk and involvement in these processes. Still more research in this realm is needed to substantiate these hypotheses.

6.2. Transcriptional Regulation of Lipid Metabolism and Trafficking

ESRRA has demonstrated transcriptional control over several genes involved in virtually all stages of energy metabolism. Moreover, ESRRA plays a fundamental role in lipid homeostasis, as it is highly expressed in tissues that derive energy from fatty acid metabolism, and thus, likely contributes to the high basal levels of fatty acid utilization in these oxidative tissues [20,22,24,26]. As mentioned earlier Acadm, is an ESRRA target gene encoding the medium-chain acyl-coenzyme A dehydrogenase (MCAD), involved in the initial step of mitochondrial fatty acid beta-oxidation. The expression levels of both ESRRA and MCAD, are tightly regulated by tissue energy demands and dictate the rate of tissue FAO, as both are expressed in tissues with high energy needs [22].

Elevating hepatic ESRRA expression in mice has also been shown to correlate with elevated very low density lipoprotein (VLDL) secretion through altered levels of cholesterol and lipid regulating genes including apolipoprotein B (Apob), microsomal triglyceride transfer protein (Mttp), and phospholipase A₂ G12B (Pla2g12b), suggesting ESRRA may play a role in lipid trafficking as VLDL secretion is significant for transporting excess lipids from the liver to adipose tissue for storage, or to other metabolic tissues for consumption [43]. This regulatory role of ESRRA in lipid trafficking may have direct implications for early – intermediate dry AMD, as there is APOB protein accumulation within drusen in both the macular and peripheral regions of the eye [44].

6.3. Transcriptional Regulation of Cellular Metabolism and Mitochondrial Biogenesis

Evidence of ESRRA as a significant regulator of energy homeostasis and cellular metabolism through modulation of lipid handling, gluconeogenesis, glycolysis, and mitochondrial respiration under various stress conditions, comes from studies in tissues including the liver, brown and white adipose tissue, muscle, and tumors [24,27]. ESRRA has been uncovered as a consistent regulator of various genes related to oxidative phosphorylation as well as a significant activator for the transcription of genes involved in mitochondrial biogenesis [20,21,24]. PGC-1α and PGC-1β, coactivators for ESRRA are involved in both mitochondrial biogenesis and oxidative phosphorylation, and ESRRA can directly interact with these coactivators to stimulate the expression of genes involved in mitochondrial biogenesis, including those encoding proteins involved in mitochondrial DNA replication, transcription, and protein import [20,22]. Furthermore, it has been demonstrated that decreased levels of ESRRA can lead to lowered expression of genes involved in mitochondrial function, resulting in impaired mitochondrial respiration and lower levels of ATP in melanoma cells, further solidifying the role ESRRA plays in promoting mitochondrial biogenesis and energy production. Failures in these interactions contribute to a variety of age-related and neurodegenerative diseases that have similar pathological pathways to AMD, including Alzheimer’s disease, Parkinson’s disease, and osteoarthritis, as well as AMD itself [15,20,22,45].

6.4. Inflammation

ESRRA deficiency exacerbates systemic inflammatory responses in vivo [22,43]. ESRRA activation has been demonstrated to exert anti-inflammatory effects by suppressing the activity of nuclear factor kappa B (NF-κB), a transcription factor important in regulating the expression of inflammatory genes in various tissues including human aortic endothelial cells and bone marrow derived macrophages in mouse models [46,47]. Mechanistically, ESRRA can inhibit NF-κB signaling by promoting the degradation of the NF-κB subunit p65 in the nucleus. This crosstalk results in reduced production of pro-inflammatory cytokines including TNFα and interleukin-6 as well as in reduced toll-like receptor (TLR)-induced inflammation [48]. ESRRA has also been shown to enhance the expression of antioxidant enzymes such as superoxide dismutase 2 (SOD2) and genes involved in mitochondrial biogenesis, helping to reduce oxidative stress and inflammation in neurons, cardiomyocytes, myocytes, and malignant cells [49]. The potential roles of NF-kB, SOD2, and TLRs have not only been studied extensively in AMD, using in vitro and in vivo models [50,51], but also in genetic studies, with loci identified near SOD2 and in NF-kB reportedly associated with increased risk for AMD in a Chinese population [52].

6.5. Angiogenesis

ESRRA has been shown to inhibit VEGF, a key pro-angiogenic factor that stimulates the growth and migration of endothelial cells, in a cell specific manner by binding to specific promoters / regulatory regions of the VEGF gene and suppressing their transcription [53]. In contrast, ESRRA induces VEGF in other tissues, particularly carcinomic cells, and PGC-1α in choroidal cells, indicating that future research into the role of ESRRA in choroidal neovascularization would provide important insight into the role of ESRRA in wet AMD [54,55].

6.6. Senescence

Various studies have demonstrated that ESRRA, PCG1-a, and their mitochondrial regulatory target genes decrease in expression with age in renal, skeletal, and hippocampus tissue [56–58]. Furthermore, a functional study in mice demonstrated that ESRRA activation, through a ligand/agonist and caloric restriction, reverses age-related mitochondrial dysfunction, cellular senescence, and inflammation in the aging kidney [58]. Additionally, mTOR, a known collaborator with ESRRA, is a central regulator of cellular aging by its modulation of cellular growth, autophagy, and protein translation [56]. Further research is needed to illuminate how ESRRA expression is modulated by age in ocular tissues and the extent to which senescence plays a role in the different clinical subtypes of AMD [59].

7. ESRRA’s Involvement in Systemic and Neurodegenerative Diseases

7.1. ESRRA and Alzheimer’s Disease

AMD has been linked to other neurodegenerative diseases, particularly Alzheimer’s disease (AD), in which AMD patients have an approximately 1.3-fold increased risk as compared to people without AMD [60]. This association is also supported by the overlap in pathogenic pathways between the two conditions including chronic inflammation, mitochondrial dysfunction, and elevated continuous oxidative stress [16,57]. The exact nature of this association is not well understood, but it is thought that shared risk factors may also contribute to the link between the two diseases [61]. Similarly for Parkinson’s disease another neurodegenerative disease, a neuronal transcriptional circuit regulated by PGC-1α and ESRRA has been suggested as a therapeutic target though how this feed forward circuit can be targeted through pharmaceuticals has not been clearly delineated [62].

7.2. ESRRA and Diabetes

Diabetes mellitus, though not a risk factor for AMD, has been correlated to ocular disease and potentially AMD in its late stages [63]. A study using genome-wide expression analysis discovered that individuals who are pre-diabetic or diabetic have reduced expression of genes related to mitochondrial oxidative phosphorylation (OXPHOS) when compared to healthy individuals [64]. These genes are controlled by the transcriptional co-activator PGC-1α, and ESRRA is recruited by PGC-1α to regulate the OXPHOS transcriptional program that is altered in diabetic muscle, suggesting that ESRRA is a potential target for type 2 diabetes [22]. ESRRA is a sought-after therapeutic target for diabetes mellitus as it plays a major role in the transcriptional regulation of insulin and changes in its expression and recruitment of cofactors could be linked to pathological changes in diabetes [26].

8. Conclusions and next steps

Though the hypothesis of targeting ESRRA holds promise as a therapeutic strategy for the different stages of AMD, there remains a gap in the literature to be filled in its support. Important questions to be addressed regarding the role of ESRRA in the eye during aging and in AMD include: How is ESRRA expression and activity in retinal cells affected by oxidant or dietary insults including smoking and consumption of lipid- and cholesterol-rich diets? Is ESRRA a regulator of lipid trafficking or inflammation in the eye? To what extent does its activity regulate RPE and choroidal endothelial cellular metabolism under baseline conditions versus hypoxia? Does ESRRA activation promote or hinder mitochondrial biogenesis and oxidative metabolism in the eye? Or cellular lipofuscin levels? Is there cross-talk between the ESRR isoforms in the different retinal cells? What role does ESRRA play in angiogenesis? Does activation or antagonism of the receptor or composition of co-regulators vary in the ocular cells vulnerable in AMD such as RPE cells, choroidal endothelial cells, immune cells, photoreceptors, and microglial cells? From a therapeutic perspective in vitro and in vivo model systems are tools that can be used to determine if therapy should be considered in a cell directed manner. Finally, given ESRRA is an orphan nuclear receptor, not only is identifying pharmacological drugs able to agonize or antagonize this receptor paramount, but also determining if targeting coregulators of ESRRA may be considered as an option, in the absence of bona fide ligand – activating drugs.

Abbreviations

AD

Alzheimer’s disease

AMD

Age-related macular degeneration

ApoB –

Apolipoprotein B

BMI

Body mass index

ESRR

Estrogen related receptor

FDA

Food and drug administration

GA

Geographic atrophy

HIF-1α

Hypoxia-Inducing Factor 1-α

LXR

Liver X receptor

MCAD

Medium-chain acyl-coenzyme A dehydrogenase

MTTP

Microsomal triglyceride transfer protein

NCOR1

Nuclear receptor corepressor 1

NF-κB

Nuclear factor kappa B

NR

Nuclear receptor

Nurr1

Nuclear receptor related 1

OXPHOS

Oxidative phosphorylation

PEDF

Pigment epithelium-derived factor

PGC1α

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

Pla2g12b

Phospholipase A2 G12B

PPAR

Peroxisome proliferator activated receptor

ROR

Retinoid X receptor orphan receptor

ROS

Reactive oxygen species

RPE

Retinal pigment epithelium

SOD

Superoxide dismutase

TLR

Toll like receptor

TNF

Tumor necrosis factor

VEGF

Vascular endothelial growth factor

VLDL

Very low density lipoprotein