title: Deregulation of cdk5 in Hippocampal sclerosis.
abstract: Hippocampal sclerosis (HS) is the most common cause of chronic medically refractory epilepsy in adults. Histologically, HS is characterized by segmental neuronal loss and gliosis. Although neuronal loss is important to the pathophysiology of HS, the molecular mechanisms underlying the neuronal loss remain uncertain. Recently, it has been appreciated that proteins important in neurodevelopment may also have a role in neurodegeneration. Cyclin-dependent kinase 5 (cdk5), known to be crucial in development of the normal cerebral cortex, has now been shown as pivotal in several cell death paradigms, including apoptosis and necrosis. Deregulation of cdk5 by p25 causes hyperphosphorylation of tau and may contribute to pathology in several neurodegenerative conditions. Furthermore, it has been shown that after transient forebrain ischemia, cdk5 causes specific death of CA1 neurons in the rat hippocampus by direct phosphorylation of the NR2A subunit of the NMDA receptor and subsequent excitotoxicity. Because apoptosis, necrosis, and excitotoxicity are all thought to contribute to neuronal loss in HS, we hypothesized that abnormalities of the cdk5 pathway would accompany this disorder. Surgically resected cases of HS with adjacent histologically normal lateral temporal cortex were examined for cdk5 and its activator p35/p25. We consistently found increased immunoreactivity for p35/p25 in surviving neurons within areas of neuronal loss compared with areas where neurons were preserved. Western blots showed the ratio of p25 to p35 to be greater in diseased hippocampi than in the adjacent histologically normal temporal lobe. Histone-based kinase assays demonstrated increased activity of the p25-cdk5 complex in HS compared with the temporal lobe despite neuronal loss in the hippocampal samples. Our results suggest that p25 is pathologically increased in HS and that deregulation of cdk5 by p25 might contribute to neuronal death in this condition.
authors.affiliation: Department of Clinical and Experimental Epilepsy, The Institute of Neurology, University College London, Queen Square, London, U.K.
authors.forename: Arjune
authors.initials: A
authors.lastname: Sen
authors.forename: Maria
authors.initials: M
authors.lastname: Thom
authors.forename: Lillian
authors.initials: L
authors.lastname: Martinian
authors.forename: Tom
authors.initials: T
authors.lastname: Jacobs
authors.forename: Margareta
authors.initials: M
authors.lastname: Nikolic
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Sisodiya
mesh_terms: D000328:Adult; D015153:Blotting, Western / Q000379:methods; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D004827:Epilepsy / Q000150:complications / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D012598:Sclerosis / Q000209:etiology / Q000473:pathology
chemical_list: D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5; D010751:Phosphopyruvate Hydratase