α-Synuclein-mediated inhibition of ATF6 processing into COPII vesicles disrupts UPR signaling in Parkinson's disease

Neurobiology of Disease
Joel J CredleAnita Sidhu

Abstract

The unfolded protein response (UPR) monitors the folding environment within the endoplasmic reticulum (ER). Accumulation of misfolded proteins within the ER activates the UPR resulting in the execution of adaptive or non-adaptive signaling pathways. α-Synuclein (α-syn) whose accumulation and aggregation define the pathobiology of Parkinson's disease (PD) has been shown to inhibit ER-Golgi transit of COPII vesicles. ATF6, a protective branch of the UPR, is processed via COPII mediated ER-Golgi transit following its activation via ER stress. Using cellular PD models together with biochemical reconstitution assays, we showed that α-syn inhibited processing of ATF6 directly through physical interactions and indirectly through restricted incorporation into COPII vesicles. Impaired ATF6 signaling was accompanied by decreased ER-associated degradation (ERAD) function and increased pro-apoptotic signaling. The mechanism by which α-syn inhibits ATF6 signaling expands our understanding of the role ER stress and the UPR play in neurodegenerative diseases such as PD.

References

Jan 1, 1990·Annual Review of Cell Biology·R D KlausnerJ S Bonifacino
Jul 23, 1999·Toxicological Sciences : an Official Journal of the Society of Toxicology·D L Eaton, T K Bammler
Jan 4, 2003·Nature Reviews. Neuroscience·Gonzalo E TorresMarc G Caron
Feb 15, 2003·Developmental Cell·Hiderou YoshidaKazutoshi Mori
Feb 25, 2003·The Journal of Biological Chemistry·William Andrew Holtz, Karen Laurel O'Malley
Jan 20, 2005·Molecular and Cellular Biology·Jingshi ShenRon Prywes
Aug 17, 2005·Human Molecular Genetics·Victoria Menéndez-BenitoNico P Dantuma
Oct 26, 2005·Molecular Cell·Bertrand KleizenIneke Braakman
Feb 23, 2007·Molecular Biology of the Cell·Mikael LernerOlle Sangfelt
Jun 15, 2007·Nature Reviews. Molecular Cell Biology·David Ron, Peter Walter
Nov 10, 2007·Science·Jonathan H LinPeter Walter
Oct 14, 2009·Proceedings of the National Academy of Sciences of the United States of America·Adam J Schindler, Randy Schekman
Aug 10, 2010·The Journal of Biological Chemistry·Jobin VarkeyRalf Langen
Dec 17, 2010·Human Molecular Genetics·Lijun WangRaymond P Roos
Mar 15, 2011·FEBS Letters·Adam W Oaks, Anita Sidhu
Nov 22, 2011·The Journal of Pathology·Diana A T NijholtJeroen J M Hoozemans
Dec 24, 2011·Nature Cell Biology·Giulia ZanettiRandy Schekman
Mar 22, 2012·Molecular Therapy : the Journal of the American Society of Gene Therapy·Marina S GorbatyukOleg S Gorbatyuk
May 9, 2012·The International Journal of Biochemistry & Cell Biology·Jeroen J M Hoozemans, Wiep Scheper
May 31, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jose F AbisambraChad A Dickey
Apr 23, 2014·Proceedings of the National Academy of Sciences of the United States of America·Pamela ValdésClaudio Hetz

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Citations

Feb 4, 2016·Proceedings of the National Academy of Sciences of the United States of America·Joseph R MazzulliDimitri Krainc
Nov 12, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Shu-Xun LiuBo-Lin Zhang
Dec 24, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Irina MilisavSamo Ribarič
Aug 26, 2015·Journal of Molecular Neuroscience : MN·Syed Zahid Ali ShahLifeng Yang
Apr 15, 2015·Frontiers in Aging Neuroscience·Gabriela MercadoClaudio Hetz
May 2, 2016·Brain Research·Vicente ValenzuelaClaudio Hetz
Sep 30, 2016·Cellular and Molecular Life Sciences : CMLS·Syed Zahid Ali ShahLifeng Yang
Apr 3, 2016·Brain Research·Navit Ogen-ShternGerardo Z Lederkremer
Jul 22, 2017·Nature Reviews. Neurology·Claudio Hetz, Smita Saxena
Mar 8, 2016·International Journal of Molecular Sciences·Hafiz Maher Ali ZeeshanHan-Jung Chae
Dec 1, 2017·Molecular Brain·Lesly PuspitaJae-Won Shim
Oct 25, 2017·Cell and Tissue Research·Marta Cherubini, Richard Wade-Martins
Mar 13, 2019·Biology of the Cell·Alexis MartinezClaudio Hetz
Aug 28, 2019·Cold Spring Harbor Perspectives in Biology·Benjamin J AndreoneJoseph W Lewcock
Aug 5, 2020·Cytoskeleton·Wei SunYao-Chun Wang
Feb 12, 2019·Chonnam Medical Journal·Ather Muneer, Rana Mozammil Shamsher Khan
Mar 25, 2020·International Journal of Molecular Sciences·Wioletta Rozpędek-KamińskaIreneusz Majsterek
Sep 6, 2018·Molecular Neurobiology·Alberim KurtishiSimon G Møller
Jun 14, 2019·Frontiers in Neuroscience·Emanuela Colla
Aug 29, 2020·International Journal of Molecular Sciences·Rose Ghemrawi, Mostafa Khair
May 28, 2019·Frontiers in Neuroscience·Šárka LehtonenJari Koistinaho
Mar 4, 2021·Biomolecules·Talya ShachamGerardo Z Lederkremer
Aug 25, 2015·European Journal of Pharmacology·Saori TsujiiHideaki Hara
Jun 26, 2021·Frontiers in Aging Neuroscience·Haigang RenGuanghui Wang
Jun 29, 2021·Journal of Parkinson's Disease·Vera Kovaleva, Mart Saarma
Oct 12, 2021·Experimental Gerontology·Brian EvansAlexandre de Lencastre

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