Cellular compartmentalization of phosphorylated eIF2alpha and neuronal NOS in human temporal lobe epilepsy with hippocampal sclerosis.
Hippocampal sclerosis (HS) is the most common neuropathologic finding in patients with medically refractory temporal lobe epilepsy (TLE). The mechanisms resulting in neuronal injury and cell loss in HS are incompletely understood, but inhibition of protein synthesis may play a pivotal role in these processes. This study examined the relationships between two molecules known to be involved in reduced protein synthesis in animals subjected to traumatic brain injury. Translational initiation of protein synthesis is inhibited when 2alpha (eIF2alpha) is phosphorylated. Recently, nitric oxide (NO) has been shown to reduce protein synthesis by inducing phosphorylation of eIF2alpha. We performed immunocytochemistry for eIF2alpha(P) and histochemistry (NADPH-D reaction) for nitric oxide synthase (NOS) to determine the distribution of these molecules in hippocampi removed from patients undergoing anterior temporal lobectomy (ATL) for medically intractable TLE due to HS. The greatest number of eIF2alpha(P) positive cells was in the CA1 sector of the hippocampus, followed by the hilus of the dentate gyrus. NADPH-D positive neurons were observed most often in the hilus. Labeling in both instances involved neuronal cell body cytoplasm and varicose processes. Combination of both staining procedures revealed close relationships between differentially labeled neurons within the hilus. The results suggest that NO participates in the phosphorylation of eIF2alpha since we demonstrated that nNOS processes are closely related to eIF2alpha(P) positive cells. This may occur through activation of kinases such as PERK, which was recently revealed. In human, TLE protein synthesis inhibition may occur at the translational level since the eIF2alpha (P) labeling is cytoplasmic. Protein synthesis inhibition may contribute to neuronal cell injury and death in HS.
Petrov
Theodor
T
Department of Anatomy and Cell Biology, School of Medicine, Wayne State University, 540 East Canfield Ave., Detroit, MI 48201, USA. tpetrov@med.wayne.edu
Rafols
José A
JA
Alousi
Sarah S
SS
Kupsky
William J
WJ
Johnson
Robert
R
Shah
Jagdish
J
Shah
Aashit
A
Watson
Craig
C
D000293:Adolescent; D000328:Adult; D002451:Cell Compartmentation; D004833:Epilepsy, Temporal Lobe / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D015852:Eukaryotic Initiation Factor-2 / Q000096:biosynthesis*; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D009252:NADPH Dehydrogenase / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052248:Nitric Oxide Synthase Type I; D010766:Phosphorylation; D012598:Sclerosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology
D015852:Eukaryotic Initiation Factor-2; C496320:NOS1 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D009252:NADPH Dehydrogenase