Abstract

Optimal post-seizure therapy requires anticonvulsant and neuroprotectant therapeutic strategies, as both prolonged seizures (status epilepticus) and repetitive seizures occurring over time (epilepsy) cause neuronal death in brain and cognitive decline. Our data challenge assumptions on the relevant molecular pathways for such neuronal loss, revealing that Death Receptors of the extrinsic pathway are preferentially activated following seizures, which then trigger endoplasmic reticulum (ER) dysfunction. This extrinsic pathway activation occurs before any (intrinsic) mitochondria-linked cell death pathways become activated. We show protection from extrinsic pathway activation by ER-resident anti-apoptotic Bcl-w, which functions through effects on calcium regulation, attenuation of ER based pro-apoptotic Bcl-2 family protein function and inhibition of the integral ER membrane BAP31 complex.
The SPECIFIC AIMS of this project are:
Aim 1. Determine the significance and mechanism of death receptor complex activation as a cause of ER dysfunction and neuronal death following seizures.
Aim 2. Determine how Bcl-w protects against seizure-induced neuronal death via effects on the extrinsic pathway target:
Aim 3. Show the relationship between Extrinsic and Intrinsic pathway activation by seizures. To accomplish these aims we have developed a mouse model of seizure-induced brain injury, not previously available, with continual EEC seizure monitoring, permitting electrographic seizure quantitation and distinction between injurious and non-injurious seizure types. We also use an in vitro seizure model permitting single cell, calcium imaging and culture studies. With mouse modeling we will use knockouts for down regulation of apoptosis modulatory genes under study and provide up-regulation of protective gene products with adenoassociated viruses and TAT fusion proteins. We determine the effect of pharmacological and molecular manipulation of the extrinsic cell death pathway on seizure induced cell damage. Finally, using continuous video-EEC monitoring, we will investigate how prevention of neuronal damage following seizures effects the development of an epileptic phenotype. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039016-07
Application #
7068633
Study Section
Special Emphasis Panel (ZRG1-BDCN-L (90))
Program Officer
Stewart, Randall R
Project Start
1999-07-01
Project End
2010-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
7
Fiscal Year
2006
Total Cost
$350,015
Indirect Cost

  Institution

Name
Emanuel Hospital and Health Center
Department
Type
DUNS #
050973098
City
Portland
State
OR
Country
United States
Zip Code
97232

  Publications

Meller, Camie L; Meller, Robert; Simons, Roger P et al. (2014) Patterns of ubiquitylation and SUMOylation associated with exposure to anoxia in embryos of the annual killifish Austrofundulus limnaeus. J Comp Physiol B 184:235-47
Simon, Roger P; Meller, Robert; Zhou, An et al. (2012) Can genes modify stroke outcome and by what mechanisms? Stroke 43:286-91
Meller, Camie L; Meller, Robert; Simon, Roger P et al. (2012) Cell cycle arrest associated with anoxia-induced quiescence, anoxic preconditioning, and embryonic diapause in embryos of the annual killifish Austrofundulus limnaeus. J Comp Physiol B 182:909-20
Engel, Tobias; Schindler, Clara K; Sanz-Rodriguez, Amaya et al. (2011) Expression of neurogenesis genes in human temporal lobe epilepsy with hippocampal sclerosis. Int J Physiol Pathophysiol Pharmacol 3:38-47
Thompson, Simon; Pearson, Andrea N; Ashley, Michelle D et al. (2011) Identification of a novel Bcl-2-interacting mediator of cell death (Bim) E3 ligase, tripartite motif-containing protein 2 (TRIM2), and its role in rapid ischemic tolerance-induced neuroprotection. J Biol Chem 286:19331-9
Thompson, Simon J; Ashley, Michelle D; Stöhr, Sabine et al. (2011) Suppression of TNF receptor-1 signaling in an in vitro model of epileptic tolerance. Int J Physiol Pathophysiol Pharmacol 3:120-32
Engel, T; Hatazaki, S; Tanaka, K et al. (2010) Deletion of Puma protects hippocampal neurons in a model of severe status epilepticus. Neuroscience 168:443-50
Murphy, B M; Engel, T; Paucard, A et al. (2010) Contrasting patterns of Bim induction and neuroprotection in Bim-deficient mice between hippocampus and neocortex after status epilepticus. Cell Death Differ 17:459-68
Meller, Robert (2009) The role of the ubiquitin proteasome system in ischemia and ischemic tolerance. Neuroscientist 15:243-60
Murphy, Niamh; Yamamoto, Akitaka; Henshall, David C (2008) Detection of 14-3-3zeta in cerebrospinal fluid following experimentally evoked seizures. Biomarkers 13:377-84

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