Tau and Protein Phosphatase-1 in Neurodegeneration

Northwestern University, Evanston IL

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Abstract

DESCRIPTION (provided by applicant): Intracellular deposits of the microtubule-associated protein tau characterize numerous neurodegenerative conditions, including Alzheimer's disease (AD). Changes that tau undergoes during disease progression include hyperphosphorylation, truncation, and self-aggregation into filaments. The connection between tau changes and neuronal death is unknown. It has recently been discovered that tau can bind to the catalytic subunit of protein phosphatase-1 (PP1c). The in vivo function of the tau-PP1c complex is unknown, but may include the regulation of microtubule-dependent processes. Disease-related changes in tau may result in dysregulation of the tau-PP1c complex, and this dysregulation may be neurotoxic. In this proposal, a combination of binding assays and phosphatase activity assays will be used to identify the sequence(s) in tau involved in the formation of the tau-PP1c complex. These same assays will be employed to determine if the tau-PP1c interaction is sensitive to disease-related changes in the tau molecule. Finally, squid axoplasm will be used as a model system in which to explore the possible involvement of the tau-PP1c complex in the regulation of kinesin-dependent transport.