Evidence map›Paper›PMID 29212711›Full record

ArticleScience translational medicine2017

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

Audrey S Dickey, Dafne N Sanchez, Martin Arreola, Kunal R Sampat, Weiwei Fan, Nicolas Arbez, Sergey Akimov, Michael J Van Kanegan, Kohta Ohnishi, Stephen K Gilmore-Hall and 9 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Science translational medicine, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.

0numbers the graph read from it
0cells of the map it votes in
32citing papers in PubMed
3.2field-weighted citation impact, top 7% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

32 citing papers in PubMed, 81 citations in OpenAlex.

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  13. HDAC4 Inhibitors as Antivascular Senescence Therapeutics.Oxidative medicine and cellular longevity · 2022
    Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors at 4 institutions in 1 country.

Audrey S DickeyDepartment of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.ORCID http://orcid.org/0000-0001-7490-2769
Dafne N SanchezDepartment of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.ORCID http://orcid.org/0000-0002-8095-9312
Martin ArreolaDepartment of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.ORCID http://orcid.org/0000-0002-7630-1403
Kunal R SampatDepartment of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.ORCID http://orcid.org/0000-0002-0879-5421
Weiwei FanGene Expression Laboratory, Salk Institute for Biological Studies, San Diego, CA 92037, USA.ORCID http://orcid.org/0000-0002-1347-7321
Nicolas ArbezDepartments of Psychiatry, Neurology, and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.ORCID http://orcid.org/0000-0003-1038-192X
Sergey AkimovDepartments of Psychiatry, Neurology, and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.ORCID http://orcid.org/0000-0002-7135-0361
Michael J Van KaneganCenter for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.ORCID http://orcid.org/0000-0002-7978-3241
Kohta OhnishiDepartment of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.ORCID http://orcid.org/0000-0002-6761-2736
Stephen K Gilmore-HallDepartment of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.ORCID http://orcid.org/0000-0001-5919-2033
April L FloresDepartment of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.ORCID http://orcid.org/0000-0001-6472-9093
Janice M NguyenDepartment of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Nicole LomasDepartment of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.ORCID http://orcid.org/0000-0002-4213-4344
Cynthia L HsuDepartment of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.ORCID http://orcid.org/0000-0002-2604-1340
Donald C LoCenter for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Christopher A RossDepartments of Psychiatry, Neurology, and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Eliezer MasliahDepartment of Pathology, University of California, San Diego, La Jolla, CA 92093, USA.
Ronald M EvansGene Expression Laboratory, Salk Institute for Biological Studies, San Diego, CA 92037, USA.ORCID http://orcid.org/0000-0002-9986-5965
Albert R La SpadaDepartment of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA. alaspada@ucsd.edu.ORCID http://orcid.org/0000-0001-6151-2964
University of California San Diego · USJohns Hopkins University · USDuke University · USSalk Institute for Biological Studies · US

Funding

Viral Vector Core (VVC)P30CA014195 · NCI · SALK INSTITUTE FOR BIOLOGICAL STUDIES · PI Ye Zheng · 1985 to 2026
$82.8M
Yeast Genetics and Stress Response Genes-BiomedicalP42ES010337 · NIEHS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI TUKEY, ROBERT H · 2000 to 2022
$69.8M
MEDICAL SCIENTIST TRAINING PROGRAMT32GM007198 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI CHI, NEIL C, INSEL, PAUL A · 1985 to 2024
$29.3M
Transcriptional GenomicsP01HL088093 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI WITZTUM, JOSEPH L. · 2008 to 2018
$26.4M
HORMONAL REGULATION OF MAMMALIAN GENE EXPRESSIONR37DK057978 · NIDDK · SALK INSTITUTE FOR BIOLOGICAL STUDIES · PI EVANS, RONALD M · 2000 to 2019
$16.0M
The PPAR-delta pathway in neural function and Huntington's disease neuropathologyR01NS065874 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI LA SPADA, ALBERT R · 2010 to 2020
$4.0M
Spatial Regulation of Developmental Gene ExpressionR01HL105278 · NHLBI · SALK INSTITUTE FOR BIOLOGICAL STUDIES · PI EVANS, RONALD M · 2011 to 2019
$4.0M
Molecular genetic regulation of autophagy in health and neurodegenerative diseaseR01AG033082 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI LA SPADA, ALBERT R · 2009 to 2019
$4.0M
Molecular Mechanisms of Inflammation, Steatosis and Hepatic Insulin ResistanceR24DK090962 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI OLEFSKY, JERROLD MICHAEL · 2010 to 2011
$1.5M
Modulation of the PPAR-delta Signaling Pathway in Huntingtons DiseaseF32NS081964 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI DICKEY, AUDREY S · 2012 to 2014
$157k
NCI NIH HHS P30 CA014195NHLBI NIH HHS P01 HL088093NHLBI NIH HHS R01 HL105278NIA NIH HHS R01 AG033082NIDDK NIH HHS R24 DK090962NIDDK NIH HHS R37 DK057978NIEHS NIH HHS P42 ES010337NIGMS NIH HHS T32 GM007198NINDS NIH HHS F32 NS081964NINDS NIH HHS R01 NS065874
6 · The paper itself

Abstract

Neurons must maintain protein and mitochondrial quality control for optimal function, an energetically expensive process. The peroxisome proliferator-activated receptors (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 U.S. Food and Drug Administration-approved drug bexarotene. 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 neurodegenerative diseases.

Indexed as

AnimalsBexaroteneGene Expression RegulationHomeostasisHumansHuntington DiseaseMiceMuscle, SkeletalNeuronsPPAR deltaRatsRats, Sprague-DawleyReverse Transcriptase Polymerase Chain ReactionSignal TransductionTetrahydronaphthalenesBexarotenePPAR deltaTetrahydronaphthalenes

Identifiers

PMID29212711
PMCPMC5748332
OpenAlexW2775003592

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.