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

Neurobiol Dis. 2015 Apr:76:112-125. doi: 10.1016/j.nbd.2015.02.005. Epub 2015 Feb 26.

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.

Keywords: ATF6; COPII; Endoplasmic reticulum-associated degradation; Neurodegeneration; Parkinson's disease; Unfolded protein response; XBP1; α-Synuclein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / metabolism*
  • COP-Coated Vesicles / metabolism*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Endoplasmic Reticulum Stress
  • Endoplasmic Reticulum-Associated Degradation
  • Humans
  • Neurons / metabolism
  • Parkinson Disease / metabolism*
  • Signal Transduction
  • Substantia Nigra / metabolism
  • Unfolded Protein Response*
  • alpha-Synuclein / metabolism*

Substances

  • ATF6 protein, human
  • Activating Transcription Factor 6
  • alpha-Synuclein