Endoplasmic reticulum stress and apoptosis signaling in human temporal lobe epilepsy.
Apoptosis signaling pathways are implicated in the pathogenesis of temporal lobe epilepsy (TLE), but the role of endoplasmic reticulum (ER) stress and ER-localized apoptosis signaling components remains largely unexplored. Presently, we investigated ER stress and ER localization of proapoptotic Bcl-2 family members and initiator and effector caspases in resected hippocampus from patients with intractable TLE and compared findings with autopsy controls. Hippocampal immunoreactivity for KDEL (Lys-Asp-Glu-Leu), a motif in ER stress chaperones glucose-regulated proteins 78 and 94, and calnexin, was significantly higher in TLE hippocampus compared with controls. The ER-containing microsomal fraction in control brain contained Bid, Bim, and caspase 3, whereas Bad and caspases 6, 7, and 9 were very low or absent. In contrast, caspases 6, 7, and 9 were present within the microsomal fraction of TLE brain. Furthermore, cleaved caspases 7 and 9 were detected in TLE samples but not controls, and KDEL-expressing neurons coexpressed cleaved caspase 9. Potentially adaptive changes were also detected, including lowered Bim levels in this fraction, and binding of caspase 7 to the X-linked inhibitor of apoptosis protein. These data suggest seizures may induce ER stress and trigger proapoptotic signaling pathways in the ER that are counteracted by antiapoptotic signals in chronic human TLE.
Yamamoto
Akitaka
A
Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon, USA.
Murphy
Niamh
N
Schindler
Clara K
CK
So
Norman K
NK
Stohr
Sabine
S
Taki
Waro
W
Prehn
Jochen H M
JH
Henshall
David C
DC
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D037281:Calnexin / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002458:Cell Fractionation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D018384:Oxidative Stress; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C494819:BAD protein, human; C000606775:BCL2L11 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D000072224:Bcl-2-Like Protein 11; C489304:KDELR1 protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018000:Receptors, Peptide; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051025:bcl-Associated Death Protein; D037281:Calnexin; D020169:Caspases