TY - JOUR
T1 - Dopaminergic neurotoxins induce cell death by attenuating NF-κB-mediated regulation of TRPC1 expression and autophagy
AU - Sukumaran, Pramod
AU - Sun, Yuyang
AU - Antonson, Neil
AU - Singh, Brij B.
N1 - Funding Information:
The authors thank the Confocal Facility at the University of North Dakota, which is partially supported by the U.S. National Institutes of Health (NIH) Centers of Biomedical Research Excellence (COBRE; Grant P30GM103329). This work was supported by the NIH, National Institute of Dental and Craniofacial Research (Grants R01DE017102, R01DE022765, and R21DE024300), and the NIH National Institute of General Medical Sciences (NIGMS; Grant P20GM113123 to B.B.S.). The Flow Cytometer Core is supported by NIH/NIGMS Grants P20GM103442 and P20GM113123. The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB.
PY - 2018/3
Y1 - 2018/3
N2 - Alterations in Ca2+ homeostasis affect neuronal survival. However, the identity of Ca2+ channels and the mechanisms underlying neurotoxin-induced neuronal degeneration are not well understood. In this study, the dopaminergic neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridiumions (MPP+)/1-methyl- 4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), whichmimic Parkinson's disease (PD), induced neuronal degeneration by decreasing store-mediated Ca2+ entry. The function of the transient receptor potential canonical (TRPC)-1 channel wasdecreaseduponexposure to the neurotoxins, followedby a decrease inTRPC1expression.Similar toneurotoxins, samples from patients with PD exhibited attenuated TRPC1 expression, which was accompanied by a decrease in autophagic markers and a subsequent increase in apoptosis markers. Furthermore, exposure to neurotoxins attenuated PKC phosphorylation, decreased expression of autophagic markers, and increased apoptosis in SHSY-5Y neuroblastoma cells, which was again dependent on TRPC1. Prolonged neurotoxin treatment attenuated the binding of NF-κBto theTRPC1 promoter, which resulted in a decrease inTRPC1 expression, thereby attenuating autophagy and activating cell death. Restoration of TRPC1 expression rescued the effects of the dopaminergic neurotoxins in neuroblastoma cells by increasing Ca2+ entry, restoring NF-kB activity, and promoting autophagy. Overall, these results suggest that dopaminergic neurotoxins initially decreased Ca2+ entry, which inhibited the binding of NF-κB to the TRPC1 promoter, thereby inhibiting TRPC1 expression and resulting in cell death by preventing autophagy.
AB - Alterations in Ca2+ homeostasis affect neuronal survival. However, the identity of Ca2+ channels and the mechanisms underlying neurotoxin-induced neuronal degeneration are not well understood. In this study, the dopaminergic neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridiumions (MPP+)/1-methyl- 4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), whichmimic Parkinson's disease (PD), induced neuronal degeneration by decreasing store-mediated Ca2+ entry. The function of the transient receptor potential canonical (TRPC)-1 channel wasdecreaseduponexposure to the neurotoxins, followedby a decrease inTRPC1expression.Similar toneurotoxins, samples from patients with PD exhibited attenuated TRPC1 expression, which was accompanied by a decrease in autophagic markers and a subsequent increase in apoptosis markers. Furthermore, exposure to neurotoxins attenuated PKC phosphorylation, decreased expression of autophagic markers, and increased apoptosis in SHSY-5Y neuroblastoma cells, which was again dependent on TRPC1. Prolonged neurotoxin treatment attenuated the binding of NF-κBto theTRPC1 promoter, which resulted in a decrease inTRPC1 expression, thereby attenuating autophagy and activating cell death. Restoration of TRPC1 expression rescued the effects of the dopaminergic neurotoxins in neuroblastoma cells by increasing Ca2+ entry, restoring NF-kB activity, and promoting autophagy. Overall, these results suggest that dopaminergic neurotoxins initially decreased Ca2+ entry, which inhibited the binding of NF-κB to the TRPC1 promoter, thereby inhibiting TRPC1 expression and resulting in cell death by preventing autophagy.
KW - Apoptosis
KW - Calcium
KW - Calcium channels
KW - PD
KW - SOCE
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UR - http://www.scopus.com/inward/citedby.url?scp=85043593510&partnerID=8YFLogxK
U2 - 10.1096/fj.201700662RR
DO - 10.1096/fj.201700662RR
M3 - Article
C2 - 29150520
AN - SCOPUS:85043593510
SN - 0892-6638
VL - 32
SP - 1640
EP - 1652
JO - FASEB Journal
JF - FASEB Journal
IS - 3
ER -