Event Abstract

Back to Event

Activation of the Unfolded Protein Response in Parkinson's disease

Andreia N. Carvalho1, 2, Catarina Ranito1, Carolina P. Tavares1, Margarida Castro-Caldas1, 3, Elsa Rodrigues1, 2, Jorge L. Ruas4, Jack Van Horssen5 and Maria J. Gama1, 2*
  • 1 Research Institute for Medicines (iMed.ULisboa), Portugal
  • 2 Faculdade de Farmácia, Universidade de Lisboa, Portugal
  • 3 UCIBIO-REQUIMTE, Department of Life Sciences, Faculty of Science and Technology, Universidade Nova de Lisboa, Portugal
  • 4 Department of Physiology and Pharmacology, Karolinska Institutet, Sweden
  • 5 Department of Molecular Cell Biology and Immunology, VU University Medical Center, Netherlands

Mitochondrial dysfunction and proteolytic pathways failure are core contributing factors to neurodegeneration in Parkinson’s disease (PD) and lead to accumulation of misfolded oxidized proteins causing endoplasmic reticulum (ER) stress. Homeostasis reestablishment upon ER stress is dependent on the unfolded protein response (UPR). The protein kinase R-like ER kinase (PERK), one of the main effectors of the UPR, is activated upon ER stress and phosphorylates the eukaryotic translation initiation factor 2 alpha (eIF2alpha). Phosphorylation of eIF2alpha leads to a decrease in global protein synthesis, preventing an additional overload of the ER, and in parallel leads to the induction of selected genes, including the activating transcription factor 4 (ATF4), that together promote cellular recovery. Peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 alpha (PGC-1alpha), a key regulator of mitochondrial biogenesis and metabolism was shown to function as a co-supressor of the spliced form of X-box binding protein (XBP1s), another important effector of the UPR. Herein we evaluated the expression levels of ER stress markers in human PD brains and in a neurotoxin-induced PD mouse model. The potential rescuing effect of TUDCA, a chemical chaperone that enhances ER adaptive capacity, was assessed. Our results show that oxidative stress, induced by the neurotoxin MPTP, leads to the induction of the PERK branch of the UPR as evaluated by the increased levels of pPERK and peIF2alpha. TUDCA treatment reverted this effect. XBP1s mRNA and protein levels in response to MPTP administration were also assessed and correlated with PGC-1alpha expression. Overall our results contribute to further elucidate the role of ER stress in the physiopathology of PD.

Acknowledgements

This work was supported by FEDER and national funds from Fundação para a Ciência e Tecnologia (FCT): PTDC/NEU-OSD/0502/2012, PTDC/MED-FSL/30104/2017, UID/DTP/04138/2013 and fellowship SFRH/BPD/98023/2013 (to ANC).

Keywords: Parkinson's disease (PD), Neurodegenaration, Endoplasmic reticulum stress (ER stress), unfolded protein response (UPR), Protein-kinase RNA-like ER kinase (PERK)

Conference: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019), Lisboa, Portugal, 30 May - 1 Jun, 2019.

Presentation Type: Poster presentation

Topic: Cellular and Molecular Neurosciences

Citation: Carvalho AN, Ranito C, Tavares CP, Castro-Caldas M, Rodrigues E, Ruas JL, Van Horssen J and Gama MJ (2019). Activation of the Unfolded Protein Response in Parkinson's disease. Front. Cell. Neurosci. Conference Abstract: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019). doi: 10.3389/conf.fncel.2019.01.00051

Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters.

The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated.

Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed.

For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions.

Received: 28 Feb 2019; Published Online: 27 Sep 2019.

* Correspondence: PhD. Maria J Gama, Research Institute for Medicines (iMed.ULisboa), Lisboa, Portugal, mjgama@ff.ulisboa.pt