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Omega-3s for an active brain

Activation of the nuclear receptor PPARα in mice is neuroprotective and boosts memory. Liu et al. found an endogenous ligand for PPARα in the brain that may promote these effects. Proteomic analysis of rodent brain lysates and biophysical assays revealed that 7(S)-HDHA, a hydroxylated derivative of the omega-3 fatty acid DHA, bound to PPARα with high affinity. Treating primary cortical neurons with 7(S)-HDHA promoted dendritic outgrowth and arborization, as well as the expression of PPARα target genes that are associated with synaptic plasticity. Supplementing the diet of young male rats with DHA increased the amount of 7(S)-HDHA in the cortex. The findings further support the notion that omega-3 fatty acids may support synaptic function in the brain and show a potential mechanism underlying such benefits from dietary DHA.

Abstract

The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) is emerging as an important target in the brain for the treatment or prevention of cognitive disorders. The identification of high-affinity ligands for brain PPARα may reveal the mechanisms underlying the synaptic effects of this receptor and facilitate drug development. Here, using an affinity purification–untargeted mass spectrometry (AP-UMS) approach, we identified an endogenous, selective PPARα ligand, 7(S)-hydroxy-docosahexaenoic acid [7(S)-HDHA]. Results from mass spectrometric detection of 7(S)-HDHA in mouse and rat brain tissues, time-resolved FRET analyses, and thermal shift assays collectively revealed that 7(S)-HDHA potently activated PPARα with an affinity greater than that of other ligands identified to date. We also found that 7(S)-HDHA activation of PPARα in cultured mouse cortical neurons stimulated neuronal growth and arborization, as well as the expression of genes associated with synaptic plasticity. The findings suggest that this DHA derivative supports and enhances neuronal synaptic capacity in the brain.

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Supplementary Materials

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Figs. S1 to S14
Tables S1 to S4
Reference (64)

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Science Signaling
Volume 15 | Issue 741
July 2022

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Received: 19 January 2022
Accepted: 13 June 2022

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Acknowledgments

J.L. was supported by a Charles H. Best Postdoctoral Fellowship and Precision Medicine Initiative (PRiME) Fellowship. C.S. is a recipient of a postgraduate scholarship from the Ministry of National Education, Republic of Turkey. We acknowledge the support from Canadian Institutes of Health Research, instrumentation grants from the Canada Foundation for Innovation, the Ontario Research Fund, and the NSERC Research Tools and Instrument Grant. G.P. acknowledges support from the Ontario Institute for Cancer Research and its funding from the Government of Ontario. The study was supported directly by the following grants: Canadian Institutes of Health Research OME-142884 (to H.M.K.), New Frontiers in Research Fund NFRFE-2019-00901 (to H.M.K., H.P., and C.L.C.), Canadian Institutes of Health Research PJT-156159 (to A.O. and C.L.C.), Canadian Institutes of Health Research FRN-148455 (to L.A.), Canadian Institutes of Health Research MOP119421 and PJT-155959 (to Z.J.), and Natural Science and Engineering Research Council of Canada RGPIN-341498 and RGPIN-2017-06295 (to Z.J.).
Author contributions: Study conceptualization was done by H.M.K., C.L.C., Z.J., and L.A. Methodology was developed by J.L. and H.P. Investigations were performed by J.L., C.S., L.M., M.Z., A.H.M., and G.P. Visualization was done by S.A. Supervision was provided by H.M.K., H.P., C.L.C., L.A., A.O., and R.P.B. The manuscript was written by J.L. and revised and edited by H.M.K. and C.L.C.
Competing interests: The authors declare that they have no competing interests.
Data and materials availability: Metabolomic data are publicly available in MassIVE, under dataset identifier MSV000085183. All other data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.

Authors

Affiliations

Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
Roles: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Cigdem Sahin
Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON M5S 3M2, Canada.
Roles: Conceptualization, Formal analysis, Investigation, Methodology, and Validation.
Department of Biochemistry, University of Toronto, Toronto, ON M5S 3E2.
Roles: Formal analysis, Investigation, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Lilia Magomedova
Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON M5S 3M2, Canada.
Roles: Conceptualization, Investigation, Methodology, and Writing - original draft.
Minhao Zhang
Department of Chemistry, York University, Toronto, ON M3J 1P3, Canada.
Roles: Investigation and Resources.
Zhengping Jia
Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Roles: Formal analysis, Methodology, Resources, and Visualization.
Adam H. Metherel
Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Roles: Investigation, Methodology, Resources, and Writing - review & editing.
Department of Chemistry, York University, Toronto, ON M3J 1P3, Canada.
Roles: Project administration, Resources, and Supervision.
Gennady Poda
Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON M5S 3M2, Canada.
Drug Discovery, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
Roles: Data curation, Formal analysis, Methodology, Resources, Software, Visualization, Writing - original draft, and Writing - review & editing.
Richard P. Bazinet
Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Roles: Conceptualization, Investigation, Methodology, Resources, and Writing - review & editing.
Department of Biochemistry, University of Toronto, Toronto, ON M5S 3E2.
Roles: Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Validation, Visualization, and Writing - review & editing.
Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON M5S 3M2, Canada.
Roles: Conceptualization, Funding acquisition, Methodology, Resources, Supervision, Validation, and Writing - review & editing.
Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
School of the Environment, University of Toronto, Toronto, ON M5S 3H6, Canada.
Roles: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Roles: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Writing - original draft, and Writing - review & editing.

Funding Information

New Frontiers in Research Fund: NFRFE-2019-00901
New Frontiers in Research Fund: NFRFE-2019-00901
New Frontiers in Research Fund: NFRFE-2019-00901
Natural Science and Engineering Research Council of Canada: RGPIN-2017-06295

Notes

*
Corresponding author. Email: [email protected] (H.M.K.); [email protected] (H.P.)

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