Abnormal expression of cdk5 in focal cortical dysplasia in humans.
ABSTRACT Focal cortical dysplasia (FCD) is an important cause of refractory epilepsy in humans. The origin of its pathognomonic abnormal cell types and the links between abnormal cell morphology and epileptogenicity remain unknown. The developmentally-regulated kinase cdk5 and its neuronal activator p35 are known to be central to a number of key components in neuronal development, cellular morphology, cytoskeletal function, synaptic plasticity and neurodegeneration. Here we examine eight cases of human FCD for expression of cdk5. We show abnormal cdk5 immunoreactivity and aggregation of protein suggesting alterations in cdk5 may also be involved in this important epileptogenic human pathology.
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ABSTRACT: Although cyclin-dependent kinase 5 (Cdk5) is closely related to other cyclin-dependent kinases, its kinase activity is detected only in the postmitotic neurons. Cdk5 expression and kinase activity are correlated with the extent of differentiation of neuronal cells in developing brain. Cdk5 purified from nervous tissue phosphorylates neuronal cytoskeletal proteins including neurofilament proteins and microtubule-associated protein tau in vitro. These findings indicate that Cdk5 may have unique functions in neuronal cells, especially in the regulation of phosphorylation of cytoskeletal molecules. We report here generation of Cdk5(-/-) mice through gene targeting and their phenotypic analysis. Cdk5(-/-) mice exhibit unique lesions in the central nervous system associated with perinatal mortality. The brains of Cdk5(-/-) mice lack cortical laminar structure and cerebellar foliation. In addition, the large neurons in the brain stem and in the spinal cord show chromatolytic changes with accumulation of neurofilament immunoreactivity. These findings indicate that Cdk5 is an important molecule for brain development and neuronal differentiation and also suggest that Cdk5 may play critical roles in neuronal cytoskeleton structure and organization.Proceedings of the National Academy of Sciences 11/1996; 93(20):11173-8. · 9.74 Impact Factor
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ABSTRACT: The transcription factor DeltaFosB is induced in the hippocampus and other brain regions by repeated electroconvulsive seizures (ECS), an effective antidepressant treatment. The unusually high stability of this protein makes it an attractive candidate to mediate some of the long-lasting changes in the brain caused by ECS treatment. To understand how DeltaFosB might alter brain function, we examined the gene expression profiles in the hippocampus of inducible transgenic mice that express DeltaFosB in this brain region by the use of cDNA expression arrays that contain 588 genes. Of the 430 genes detected, 20 genes were consistently upregulated, and 14 genes were downregulated, by >50%. One of the upregulated genes is cyclin-dependent kinase 5 (cdk5). On the basis of its purported role in regulating neuronal structure, we studied directly whether cdk5 is a true target for DeltaFosB. Upregulation of cdk5 immunoreactivity in the hippocampus was confirmed by Western blotting in the DeltaFosB-expressing transgenic mice as well as in rats treated chronically with ECS. Chronic ECS treatment also increased, in the hippocampus, the phosphorylation state of tau, a microtubule-associated protein that is a known substrate for cdk5. A 1.6 kb fragment of the cdk5 promoter was cloned, and activity of the promoter was found to be increased after overexpression of DeltaFosB in cell culture. Moreover, mutation of the single consensus activator protein-1 site contained within the cdk5 promoter fragment completely abolished activation of the promoter by DeltaFosB. Together, these results suggest that cdk5 is one target by which DeltaFosB produces some of its physiological effects in the hippocampus and thereby mediates certain long-term consequences of chronic ECS treatment.Journal of Neuroscience 12/2000; 20(24):8965-71. · 6.91 Impact Factor
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ABSTRACT: The cytoskeletal abnormalities of cortical neurons in human cerebral cortical dysplasia were compared by immunohistochemical methods to the neurofibrillary tangles of Alzheimer's disease (AD). Surgical specimens from cortical resections performed for the treatment of intractable childhood seizures as well as autopsied samples from AD patients were analyzed with different antibodies directed against high- or medium-molecular mass neurofilament epitopes, phosphorylated or non-phosphorylated forms of neurofilaments, ubiquitin, the microtubule-associated protein tau, and paired helical filaments (PHF), a defining feature of AD tangles. A strong abnormal increase in immunoreactivity to the high and medium molecular mass neurofilament epitopes was seen in hypertrophic neurons of cortical dysplasia. These neurofilamentous accumulations of cortical dysplasia as well as AD tangles also displayed immunoreactivity with antibodies against phosphorylated and non-phosphorylated neuro-filament epitopes, tau and ubiquitin. Only the AD tangles, however, were immunoreactive to the antiserum to PHF. These results replicate and extend our previous findings that the neurofibrillary accumulations in cerebral cortical dysplasia share some common antigens with the neurofibrillary tangles of AD but do not demonstrate immunoreactivity to PHF antiserum. The results also suggest that the cytoskeletal abnormalities observed in neurons of cortical dysplasia may result in part from alterations in the level of expression, in phosphorylation state or in transport of cytoskeletal components.Acta Neuropathologica 02/1994; 87(5):493-503. · 9.73 Impact Factor