α-Synuclein-mediated inhibition of ATF6 processing into COPII vesicles disrupts UPR signaling in Parkinson's disease.
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.
Department of Biochemistry, Georgetown University Medical Center, Washington, DC 20007, USA.
Joel J
JJ
Credle
Department of Pharmacology and Physiology and Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 20007, USA.
Patrick A
PA
Forcelli
SOM Microscope Facility, Department of Cell Biology, Johns Hopkins University, Baltimore, MD 21205, USA.
Michael
M
Delannoy
Department of Biochemistry, Georgetown University Medical Center, Washington, DC 20007, USA.
Adam W
AW
Oaks
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
Eva
E
Permaul
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
Deborah L
DL
Berry
Department of Biochemistry, Georgetown University Medical Center, Washington, DC 20007, USA.
Valeriy
V
Duka
Department of Biochemistry, Georgetown University Medical Center, Washington, DC 20007, USA.
Jonathan
J
Wills
Department of Biochemistry, Georgetown University Medical Center, Washington, DC 20007, USA. Electronic address: sidhua@georgetown.edu.
Anita
A
Sidhu
D051702:Activating Transcription Factor 6 / Q000378:metabolism*; D022181:COP-Coated Vesicles / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D060746:Endoplasmic Reticulum-Associated Degradation; D006801:Humans; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*; D015398:Signal Transduction; D013378:Substantia Nigra / Q000378:metabolism; D056811:Unfolded Protein Response; D051844:alpha-Synuclein / Q000378:metabolism*
C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D051844:alpha-Synuclein
ATF6; COPII; Endoplasmic reticulum-associated degradation; Neurodegeneration; Parkinson's disease; Unfolded protein response; XBP1; α-Synuclein