Death-associated protein kinase expression in human temporal lobe epilepsy.
Experimental and human data suggest programmed (active) cell death may contribute to the progressive hippocampal atrophy seen in patients with refractory temporal lobe epilepsy. Death-associated protein (DAP) kinase is a novel calcium/calmodulin-activated kinase that functions in apoptosis mediated by death receptors. Because seizure-induced neuronal death involves both death receptor activation and calcium, we examined DAP kinase expression, localization, and interactions in hippocampal resections from patients with intractable temporal lobe epilepsy (n = 10) and autopsy controls (n = 6). Expression and phosphorylation of DAP kinase was significantly increased in epilepsy brain compared with control. DAP kinase and DAP kinase-interacting protein 1 (DIP-1) localized to mitochondria in control brain, whereas levels of both were increased in the cytoplasm and microsomal (endoplasmic reticulum) fraction in epilepsy samples. Coimmunoprecipitation analysis showed increased DAP kinase binding to calmodulin, DIP-1, and the Fas-associated protein with death domain (FADD) in epilepsy samples. Finally, immunohistochemistry determined DAP kinase was coexpressed with DIP-1 in neurons. This study provides the first description of DAP kinase and DIP-1 in human brain and suggests DAP kinase is a novel molecular regulator of neuronal death in epilepsy.
Henshall
David C
DC
Robert S. Dow Neurobiology Laboratories, Legacy Research, Neurological Sciences Center, Portland, OR, USA. dhenshall@downeurobiology.org
Schindler
Clara K
CK
So
Norman K
NK
Lan
Jing-Quan
JQ
Meller
Robert
R
Simon
Roger P
RP
D000293:Adolescent; D000328:Adult; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D064550:Death-Associated Protein Kinases; D004833:Epilepsy, Temporal Lobe / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006624:Hippocampus / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation
D051017:Apoptosis Regulatory Proteins; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases