title: Dysregulation of PINCH signaling in mesial temporal epilepsy.
abstract: Mounting evidence suggests that inflammation is important in epileptogenesis. Particularly Interesting New Cysteine Histidine-rich (PINCH) protein is a highly conserved, LIM-domain protein known to interact with hyperphosphorylated Tau. We assessed PINCH expression in resected epileptogenic human hippocampi and further explored the relationships among PINCH, hpTau and associated kinases. Resected hippocampal tissue from 7 patients with mesial temporal lobe epilepsy (MTLE) was assessed by Western analyses to measure levels of PINCH and hyperphosphorylated Tau, as well as changes in phosphorylation levels of associated kinases AKT and GSK3β in comparison to normal control tissue. Immunolabeling was also conducted to evaluate PINCH and hpTau patterns of expression, co-localization and cell-type specific expression. Hippocampal PINCH was increased by 2.6 fold in the epilepsy cases over controls and hpTau was increased 10 fold over control. Decreased phospho-AKT and phospho-GSK3β in epilepsy tissue suggested involvement of this pathway in MTLE. PINCH and hpTau co-localized in some neurons in MTLE tissue. While PINCH was expressed by both neurons and astrocytes in MTLE tissue, hpTau was extracellular or associated with neurons. PINCH was absent from the serum of control subjects but readily detectable from the serum of patients with chronic epilepsy. Our study describes the expression of PINCH and points to AKT/GSK3β signaling dysregulation as a possible pathway in hpTau formation in MTLE. In view of the interactions between hpTau and PINCH, understanding the role of PINCH in MTLE may provide increased understanding of mechanisms leading to inflammation and MTLE epileptogenesis and a potential biomarker for drug-resistant epilepsy.
authors.affiliation: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Russin
authors.affiliation: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Christianne
authors.initials: C
authors.lastname: Heck
authors.affiliation: Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA; Department of Kinesiology, College of Public Health, Philadelphia, PA, USA; Department of Kinesiology, University of Indiana, Philadelphia, PA, USA.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kawata
authors.affiliation: Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Adiga
authors.affiliation: Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Yen
authors.affiliation: Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lambert
authors.affiliation: Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Stear
authors.affiliation: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Law
authors.affiliation: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Marquez
authors.affiliation: Department of Neurology, Temple University School of Medicine, and Shriners Hospitals Pediatric Research Center, Philadelphia, PA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Crino
authors.affiliation: Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Millett
authors.affiliation: Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. Electronic address: tdl@temple.edu.
authors.forename: Dianne
authors.initials: D
authors.lastname: Langford
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D001253:Astrocytes / Q000378:metabolism; D016022:Case-Control Studies; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism*; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; C088088:LIMS1 protein, human; D008565:Membrane Proteins; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt
keywords: Hippocampal sclerosis; Hyperphosphorylated Tau; Mesial temporal lobe epilepsy; PINCH protein