PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically

Dickey, Audrey S.; Pineda, Victor V.; Tsunemi, Taiji; Liu, Patrick P.; Miranda, Helen Cristina; Gilmore-Hall, Stephen K.; Lomas, Nicole; Sampat, Kunal R.; Buttgereit, Anne; Torres, Mark Joseph Manalang; Flores, April L.; Arreola, Martin; Arbez, Nicolas; Akimov, Sergey; Gaasterland, Terry; Lazarowski, Eduardo R.; Ross, Christopher A.; Yeo, G; Sopher, Bryce L.; Magnuson, Gavin; Pinkerton, Anthony B.; Masliah, Eliezer; Spada, Albert R. La

doi:10.1038/nm.4003

Cited by 83 publications

(97 citation statements)

References 58 publications

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“…Moreover, Dickey and colleagues recently tested the PPARδ agonist KD3010 in HD N171-82Q transgenic mice. They observed improved motor function, decreased neurodegeneration and longer survival in HD mice [66].…”

Section: Discussionmentioning

confidence: 93%

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Toczek

Zielonka

Zukowska

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Huntington's disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Our recent studies showed an increased risk of heart contractile dysfunction and dilated cardiomyopathy in HD pre-clinical models. This could potentially involve metabolic remodeling, that is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. These effects may be caused locally by mutant HTT, via gain or loss of function effects, or distally by a lack of trophic signals from central nerve stimulation. Either may lead to energy equilibrium imbalances in cardiac cells, with activation of nucleotide catabolism plus an inhibition of resynthesis. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction. Importantly, we describe the first set of biomarkers related to heart and skeletal muscle dysfunction in both pre-clinical and clinical HD settings.Keywords: Huntington's disease, cardiomyopathy, arrhythmia, energy imbalance, catabolism of nucleotides, heart failure 3 SUMMARY Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related cardiomyopathy has been widely described in different mouse models, however there is little known about the source of the pathological remodelling in HD hearts. We found that contractile dysfunction in HD settings might be caused by components of cellular energy imbalance, changes in catabolism of adenine nucleotides, steady-state internal redox derangements and an activation of AMPK, leading to a shift in the cardiac substrate preference. These changes were accompanied by increased concentrations of adenine nucleotide catabolites (inosine, hypoxanthine, xanthine and uric acid) and uridine in both HD mouse models and HD patients' plasma. These metabolites represent the first identified biomarkers related to striated muscle dysfunction in HD. Our study explores a mechanism that might lead to HD-related cardiomyopathy and opens new avenues for therapeutic treatments in HD. HIGHLIGHTS• Heart dysfunction in HD is caused by the altered metabolism of nucleotides in vivo • Altered energy imbalances may lead to heart malfunction in HD in vivo• Increased lev...

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Section: Discussionmentioning

confidence: 93%

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Toczek

Zielonka

Zukowska

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Additionally, GPR52 knockdown lowered caspase 3 activity in response to BDNF withdrawal. Moreover, the number of condensed nuclei after BDNF withdrawal was reduced by peroxisome proliferator-activated receptor gamma (PPAR δ ) activator (KD3010) [92]. Many research groups have described drug effect of BDNF or FGF/LIF withdrawal, considered as a stress factor on cell survival [88].…”

Section: Ipscs Providing New Tools For Developing Treatments For Cmentioning

confidence: 99%

Generation of Cholinergic and Dopaminergic Interneurons from Human Pluripotent Stem Cells as a Relevant Tool for In Vitro Modeling of Neurological Disorders Pathology and Therapy

Ochałek

Szczesna

Petazzi

et al. 2016

Stem Cells International

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The cellular and molecular bases of neurological diseases have been studied for decades; however, the underlying mechanisms are not yet fully elucidated. Compared with other disorders, diseases of the nervous system have been very difficult to study mainly due to the inaccessibility of the human brain and live neurons in vivo or in vitro and difficulties in examination of human postmortem brain tissue. Despite the availability of various genetically engineered animal models, these systems are still not adequate enough due to species variation and differences in genetic background. Human induced pluripotent stem cells (hiPSCs) reprogrammed from patient somatic cells possess the potential to differentiate into any cell type, including neural progenitor cells and postmitotic neurons; thus, they open a new area to in vitro modeling of neurological diseases and their potential treatment. Currently, many protocols for generation of various neuronal subtypes are being developed; however, most of them still require further optimization. Here, we highlight accomplishments made in the generation of dopaminergic and cholinergic neurons, the two subtypes most affected in Alzheimer's and Parkinson's diseases and indirectly affected in Huntington's disease. Furthermore, we discuss the potential role of hiPSC-derived neurons in the modeling and treatment of neurological diseases related to dopaminergic and cholinergic system dysfunction.

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“…The importance of PGC-1α for HD pathogenesis is underscored by the observation that PGC-1α overexpression is sufficient to rescue motor dysfunction, prevent accumulation of misfolded htt protein, and stave off neurodegeneration in HD mice (9). To determine the mechanistic basis for PGC-1α transcription interference in HD, we performed an unbiased screen that showed PPARs to be htt interactors, and documented an interaction between PPARδ and htt in non-neuronal cells, in striatal-like neurons, and in the cerebral cortex of HD mice (10). We noted that PPARδ is highly expressed in neurons of the central nervous system (CNS), and demonstrated that expression of dominant-negative PPARδ in CNS is sufficient to produce motor phenotypes, neurodegeneration, mitochondrial defects, and transcriptional abnormalities that closely parallel HD disease phenotypes (10).…”

Section: Introductionmentioning

confidence: 99%

“…To determine the mechanistic basis for PGC-1α transcription interference in HD, we performed an unbiased screen that showed PPARs to be htt interactors, and documented an interaction between PPARδ and htt in non-neuronal cells, in striatal-like neurons, and in the cerebral cortex of HD mice (10). We noted that PPARδ is highly expressed in neurons of the central nervous system (CNS), and demonstrated that expression of dominant-negative PPARδ in CNS is sufficient to produce motor phenotypes, neurodegeneration, mitochondrial defects, and transcriptional abnormalities that closely parallel HD disease phenotypes (10). We then evaluated a selective, potent PPARδ agonist, KD3010, and after confirming that it crosses the blood brain barrier to up-regulate expression of PPARδ target genes in cortex and striatum, we tested KD3010 in N171-82Q transgenic mice, a rodent model of HD.…”

Section: Introductionmentioning

confidence: 99%

“…We then evaluated a selective, potent PPARδ agonist, KD3010, and after confirming that it crosses the blood brain barrier to up-regulate expression of PPARδ target genes in cortex and striatum, we tested KD3010 in N171-82Q transgenic mice, a rodent model of HD. This study established the efficacy of KD3010 PPARδ agonist therapy as a potential therapeutic approach for HD (10). …”

Section: Introductionmentioning

confidence: 99%

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PPARδ activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis

et al. 2017

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Neurons must maintain protein and mitochondrial quality control for optimal function, an energetically expensive process. The PPARs are ligand-activated transcription factors that promote mitochondrial biogenesis and oxidative metabolism. We recently determined that transcriptional dysregulation of PPARδ contributes to Huntington’s disease (HD), a progressive neurodegenerative disorder resulting from a CAG-polyglutamine repeat expansion in the huntingtin gene. We documented that the PPARδ agonist KD3010 is an effective therapy for HD in a mouse model. PPARδ forms a heterodimer with the retinoid X receptor (RXR), and RXR agonists are capable of promoting PPARδ activation. One compound with potent RXR agonist activity is the FDA-approved drug bexarotene. Here, we tested the therapeutic potential of bexarotene in HD, and found that bexarotene was neuroprotective in cellular models of HD, including medium spiny-like neurons generated from induced pluripotent stem cells (iPSCs) derived from patients with HD. To evaluate bexarotene as a treatment for HD, we treated the N171-82Q mouse model with the drug and found that bexarotene improved motor function, reduced neurodegeneration, and increased survival. To determine the basis for PPARδ neuroprotection, we evaluated metabolic function and noted markedly impaired oxidative metabolism in HD neurons, which was rescued by bexarotene or KD3010. We examined mitochondrial and protein quality control in cellular models of HD, and observed that treatment with a PPARδ agonist promoted cellular quality control. By boosting cellular activities that are dysfunctional in HD, PPARδ activation may have therapeutic applications in HD and potentially other related neurodegenerative diseases.

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PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically

Cited by 83 publications

References 58 publications

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Generation of Cholinergic and Dopaminergic Interneurons from Human Pluripotent Stem Cells as a Relevant Tool for In Vitro Modeling of Neurological Disorders Pathology and Therapy

PPARδ activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis

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