Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain

McMeekin, Laura J.; Joyce, Kathlene L.; Jenkins, Lisa M. Miller; Bohannon, Briana M; Patel, Kamlesh; Bohannon, A.S.; Patel, Aman; Fox, S.N.; Simmons, Micah; Day, Jeremy J.; Kralli, Anastasia; Crossman, David K.; Cowell, Rita M.

doi:10.1016/j.neuroscience.2021.10.007

Cited by 15 publications

(14 citation statements)

References 82 publications

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“…Similar to what we observe with Esrrg deletion in DAergic neurons, genes encoding potassium channels are also downregulated in the heart with Esrra/Esrrg knockdown 32 . Esrrg transcript expression is also enriched in GABAergic neuron populations with high expression of the calcium buffer parvalbumin 29,30 , similar to the cell type-specific expression pattern of Ppargc1a; it would be interesting to determine the transcriptional and functional consequences of Esrrg deletion in those cells.…”

Section: Discussionmentioning

confidence: 93%

“…Considering previous evidence for the neuroprotective efficacy of PGC-1α overexpression in some PD models 12,18,23,61 , we crossreferenced genes altered in Esrrg-deficient DAergic neurons with genes changed with PGC-1α overexpression in SH-SY5Y's 29 . We found that, of the genes upregulated with PGC-1α overexpression and genes downregulated with Esrrg deletion, there was an overlap of 44 genes (Fig.…”

Section: Errγ Regulates Similar Genes As Pgc-1αmentioning

confidence: 99%

“…Members of this family show sequence homology with estrogen receptors but are incapable of being bound by estrogen. All three factors have been shown to interact with PGC-1α to drive genes involved in mitochondrial structure and function [24][25][26][27][28][29] ; however, Esrrb is expressed early in development 26 , and nuclear-encoded mitochondrial genes are not significantly reduced in the midbrain brain of mice lacking Esrra 29 , leading us to explore potential roles for Esrrg in the brain. Of note, over half of the mitochondrial transcripts reduced in DAergic neurons from patients with Lewy-body pathology are direct transcriptional targets of Esrrg 12,26 .…”

Section: Introductionmentioning

confidence: 99%

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Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy

Fox

McMeekin

Savage

et al. 2022

npj Parkinsons Dis.

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Many studies implicate mitochondrial dysfunction as a key contributor to cell loss in Parkinson disease (PD). Previous analyses of dopaminergic (DAergic) neurons from patients with Lewy-body pathology revealed a deficiency in nuclear-encoded genes for mitochondrial respiration, many of which are targets for the transcription factor estrogen-related receptor gamma (Esrrg/ERRγ). We demonstrate that deletion of ERRγ from DAergic neurons in adult mice was sufficient to cause a levodopa-responsive PD-like phenotype with reductions in mitochondrial gene expression and number, that partial deficiency of ERRγ hastens synuclein-mediated toxicity, and that ERRγ overexpression reduces inclusion load and delays synuclein-mediated cell loss. While ERRγ deletion did not fully recapitulate the transcriptional alterations observed in postmortem tissue, it caused reductions in genes involved in synaptic and mitochondrial function and autophagy. Altogether, these experiments suggest that ERRγ-deficient mice could provide a model for understanding the regulation of transcription in DAergic neurons and that amplifying ERRγ-mediated transcriptional programs should be considered as a strategy to promote DAergic maintenance in PD.

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Section: Discussionmentioning

confidence: 93%

Section: Errγ Regulates Similar Genes As Pgc-1αmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy

Fox

McMeekin

Savage

et al. 2022

npj Parkinsons Dis.

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“…Following triterpenoid treatment, they showed an increased expression of Nqo1 , Gsta3 , and Hmox1 , a reduction in inflammatory markers, and an increased expression of Coxii , Esrra , Nrf1 , and Ppargc1a in the spinal cord of G93A mutant mice [ 312 ]. However, in the context of our data showing the enrichment of Nqo1 and Nfe2l2 in astrocytes and Ppargc1a and Esrra in neurons [ 291 , 313 ], it is likely that these factors activate distinct transcriptional programs in different cell types. In neurodegenerative disease, an important consideration is the impact of cell damage/loss when evaluating changes in gene expression in tissue homogenates.…”

Section: Oxidative Stress and The Transcriptional Regulation Of Antioxidant Defense Enzymes In Disease Statesmentioning

confidence: 94%

The NRF2-Dependent Transcriptional Regulation of Antioxidant Defense Pathways: Relevance for Cell Type-Specific Vulnerability to Neurodegeneration and Therapeutic Intervention

2021

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Oxidative stress has been implicated in the etiology and pathobiology of various neurodegenerative diseases. At baseline, the cells of the nervous system have the capability to regulate the genes for antioxidant defenses by engaging nuclear factor erythroid 2 (NFE2/NRF)-dependent transcriptional mechanisms, and a number of strategies have been proposed to activate these pathways to promote neuroprotection. Here, we briefly review the biology of the transcription factors of the NFE2/NRF family in the brain and provide evidence for the differential cellular localization of NFE2/NRF family members in the cells of the nervous system. We then discuss these findings in the context of the oxidative stress observed in two neurodegenerative diseases, Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), and present current strategies for activating NFE2/NRF-dependent transcription. Based on the expression of the NFE2/NRF family members in restricted populations of neurons and glia, we propose that, when designing strategies to engage these pathways for neuroprotection, the relative contributions of neuronal and non-neuronal cell types to the overall oxidative state of tissue should be considered, as well as the cell types which have the greatest intrinsic capacity for producing antioxidant enzymes.

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“… 335 Mechanically, PGC-1α activates a variety of metabolic programs in different tissues through its ability to form heteromeric complexes with many nuclear hormone receptors, such as PPARs 336 and estrogen-related receptors (ERRs). 337 Interestingly, PGC-1α is regulated by AMPK/SIRT1 axis, promoting exercise-induced tissue regeneration, as well as involved in mitochondrial signaling, 338 , 339 Thus PGC-1α has acted as a vital regulator in the adaptive response to exercise, which may be the key regulator of the cross-talk between mitochondrial biogenesis and exercise-induced regeneration (Fig. 5 ).…”

Section: Molecular Mechanisms Of Tissue Regeneration Induced By Exercisementioning

confidence: 99%

Molecular mechanisms of exercise contributing to tissue regeneration

Chen

Zhou

et al. 2022

Sig Transduct Target Ther

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Physical activity has been known as an essential element to promote human health for centuries. Thus, exercise intervention is encouraged to battle against sedentary lifestyle. Recent rapid advances in molecular biotechnology have demonstrated that both endurance and resistance exercise training, two traditional types of exercise, trigger a series of physiological responses, unraveling the mechanisms of exercise regulating on the human body. Therefore, exercise has been expected as a candidate approach of alleviating a wide range of diseases, such as metabolic diseases, neurodegenerative disorders, tumors, and cardiovascular diseases. In particular, the capacity of exercise to promote tissue regeneration has attracted the attention of many researchers in recent decades. Since most adult human organs have a weak regenerative capacity, it is currently a key challenge in regenerative medicine to improve the efficiency of tissue regeneration. As research progresses, exercise-induced tissue regeneration seems to provide a novel approach for fighting against injury or senescence, establishing strong theoretical basis for more and more “exercise mimetics.” These drugs are acting as the pharmaceutical alternatives of those individuals who cannot experience the benefits of exercise. Here, we comprehensively provide a description of the benefits of exercise on tissue regeneration in diverse organs, mainly focusing on musculoskeletal system, cardiovascular system, and nervous system. We also discuss the underlying molecular mechanisms associated with the regenerative effects of exercise and emerging therapeutic exercise mimetics for regeneration, as well as the associated opportunities and challenges. We aim to describe an integrated perspective on the current advances of distinct physiological mechanisms associated with exercise-induced tissue regeneration on various organs and facilitate the development of drugs that mimics the benefits of exercise.

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Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain

Cited by 15 publications

References 82 publications

Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy

Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy

The NRF2-Dependent Transcriptional Regulation of Antioxidant Defense Pathways: Relevance for Cell Type-Specific Vulnerability to Neurodegeneration and Therapeutic Intervention

Molecular mechanisms of exercise contributing to tissue regeneration

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