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 - 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
UR - http://www.scopus.com/inward/record.url?scp=85043593510&partnerID=8YFLogxK
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 -