Molecular and biochemical analysis of Jerky, an epilepsy related nucleic acid binding protein.

摘要

Epilepsy is a heterogeneous group of disorders that result in neuronal hyperactivity and uncontrolled seizures. These disorders can be grouped into two classes; idiopathic, arising from unknown origins, and symptomatic, arising as a secondary symptom to another primary insult. Some idiopathic epilepsies have been attributed to obvious mutations within a single family to ion channels, yet many do not have such obvious etiologies. Similarly, symptomatic epilepsies often result from heritable disorders of known origin. The Jerky protein was identified after a fortuitous disruption of the jerky gene locus resulted in a syndrome resembling temporal lobe seizures. Genetic mapping of this gene unveiled a locus adjacent to an area associated with various forms of epilepsy in humans.; Subsequent studies on Jerky revealed that a reduction in overall Jerky expression was sufficient to result in an epileptic phenotype, strengthening the similarity to idiopathic epilepsies that displayed some genetic heritability. Jerky resembled the Centromeric Binding Protein B (CENP-B) in primary amino acid sequence. It remained unclear what the true function of Jerky was until antisera raised against the protein demonstrated a divergent role from CENP-B.; This dissertation clarifies the basic role of Jerky in normal neuronal functioning as a nucleic acid binding protein. Jerky not only binds to DNA, as CENP-B would predict, but also binds to mRNA in the cytoplasm and associates with components of the translational machinery. Furthermore, Jerky is implicated in regulating translation in neurons and is additionally regulated by neuronal activity. This finding advances the understanding of basic mechanisms underlying complex diseases and also increases the knowledge of mechanisms necessary for normal functioning of cells in the nervous system.