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The unfolded protein response in the therapeutic effect of hydroxy-DHA against Alzheimer’s disease

  • THE ROLE OF SPHINGOLIPIDS AND LIPID RAFTS IN DETERMINING CELL FATE
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Abstract

The unfolded protein response (UPR) and autophagy are two cellular processes involved in the clearing of intracellular misfolded proteins. Both pathways are targets for molecules that may serve as treatments for several diseases, including neurodegenerative disorders like Alzheimer’s disease (AD). In the present work, we show that 2-hydroxy-DHA (HDHA), a docosahexaenoic acid (DHA) derivate that restores cognitive function in a transgenic mouse model of AD, modulates UPR and autophagy in differentiated neuron-like SH-SY5Y cells. Mild therapeutic HDHA exposure induced UPR activation, characterized by the up-regulation of the molecular chaperone Bip as well as PERK-mediated stimulation of eIF2α phosphorylation. Key proteins involved in initiating autophagy, such as beclin-1, and several Atg proteins involved in autophagosome maturation (Atg3, Atg5, Atg12 and Atg7), were also up-regulated on exposure to HDHA. Moreover, when HDHA-mediated autophagy was studied after amyloid-β peptide (Aβ) stimulation to mimic the neurotoxic environment of AD, it was associated with increased cell survival, suggesting that HDHA driven modulation of this process at least in part mediates the neuroprotective effects of this new anti-neurodegenerative drug. The present results in part explain the pharmacological effects of HDHA inducing full recovery of the cognitive scores in murine models of AD.

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Abbreviations

Atg:

Autophagy-related genes

AV:

Autophagic vesicle

DHA:

Docosahexenoic acid

eiF2α or eIF2α:

Eukaryotic initiation factor 2 alpha

HDHA:

2-Hydroxy-docosahexaenoic acid

IRE1:

Inositol-requiring protein 1

UPR:

Unfolded protein response

PDI:

Protein disulfide isomerase

PERK:

Protein kinase RNA-like ER kinase

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Acknowledgments

This work was supported by Grants from the Spanish Ministerio de Economía y Competitividad (BIO2010-21132, BIO2013-49006-C2-1-R, and IPT-010000-2010-16, PVE and XB), by grants to research groups of excellence from the Govern de les Illes Balears, Spain (PVE) and by the Marathon Foundation (Spain). MT was recipient of a Torres-Quevedo research contract from the Spanish Ministerio de Economía y Competitividad and the European Social Fund “Investing in your future”.  AM-E was recipient of an undergraduate fellowship from the Spanish Ministerio de Economía y Competitividad. MAF-dR was funded by a fellowship from the Govern de les Illes Balears (Conselleria d’Educació, Cultura i Universitats) operational program co-funded by the European Social Fund.

Conflict of interest

MT was supported by a Torres-Quevedo Research Contract granted to Lipopharma Therapeutics, S.L. by Ministerio de Economía y Competitividad (Spanish Government) and the European Social Fund “Investing in your future”.

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    Authors and Affiliations

    1. Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, Crta. Valldemossa km. 7.5, 07122, Palma de Mallorca, Spain

      Manuel Torres, Amaia Marcilla-Etxenike, Maria A. Fiol-deRoque, Pablo V. Escribá & Xavier Busquets

    2. Lipopharma Therapeutics S.L., Palma de Mallorca, Spain

      Manuel Torres

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    1. Manuel Torres
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    Corresponding author

    Correspondence to Pablo V. Escribá.

    Additional information

    Manuel Torres, Amaia Marcilla-Etxenike, and Maria A. Fiol-deRoque contributed equally to this work.

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    10495_2015_1099_MOESM1_ESM.tif

    SH-SY5Y neuroblastoma cell differentiation into neuron-like cells. A Representative phase-contrast micrographs (×20 magnification) of undifferentiated SH-SY5Y cells, cells maintained in the presence of RA for 5 days and SH-SY5Y cells completely differentiated with RA + hBDNF (human brain-derived neurotrophic factor). B Nestin levels determined by immunoblotting in undifferentiated (ND) and differentiated (D) SH-SY5Y cells. C Proportion of SH-SY5Y cells in Sub-G1, G1, S and G2/M phases with respect to the total cell number. D Cdk4, E Cdk6, F DHFR, G Cyclin D3 protein levels determined by immunoblotting in undifferentiated (ND) and differentiated (D) SH-SY5Y cells. Immunoblot values are expressed relative to the undifferentiated cells and each bar diagram shows the mean ± SEM. The asterisks indicate a significant difference compared to the undifferentiated cells: ***p<0.001 (TIFF 3803 kb)

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    10495_2015_1099_MOESM3_ESM.tif

    Weight of control and HDHA-treated mice. The weight of WT and 5xFAD (AD transgenic model) mice was monitored three times a week for a whole period of treatment of 3 months with HDHA at 200 mg/kg.day (or vehicle, controls) Mice treatment conditions were described previously (see references [40,41]). The data are presented as the percentage change relative to the first day of treatment. Each point shows the mean value from 4 animals ± SEM (TIFF 2525 kb)

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    Torres, M., Marcilla-Etxenike, A., Fiol-deRoque, M.A. et al. The unfolded protein response in the therapeutic effect of hydroxy-DHA against Alzheimer’s disease. Apoptosis 20, 712–724 (2015). https://doi.org/10.1007/s10495-015-1099-z

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