Biomedical subjects

William H Stoothoff

Publications and source records attributed to William H Stoothoff.

4 recordsLinked to original sources

PubMed2005

Tau phosphorylation: physiological and pathological consequences.

The microtubule-associated protein tau, abundant in neurons, has gained notoriety due to the fact that it is deposited in cells as fibrillar lesions in numerous neurodegenerative diseases, and most notably Alzheimer's disease. Regulation of microtubule dynamics is the most well-recognized function of tau, but it is becoming increasingly evident that tau plays additional roles in the cell. The functions of tau are regulated by site-specific phosphorylation events, which if dysregulated, as they are in the disease state, result in tau dysfunction and mislocalization, which is potentially followed by tau polymerization, neuronal dysfunction and death. Given the increasing evidence that a disruption in the normal phosphorylation state of tau plays a key role in the pathogenic events that occur in Alzheimer's disease and other neurodegenerative conditions, it is of crucial importance that the protein kinases and phosphatases that regulate tau phosphorylation in vivo as well as the signaling cascades that regulate them be identified. This review focuses on recent literature pertaining to the regulation of tau phosphorylation and function in cell culture and animal model systems, and the role that a dysregulation of tau phosphorylation may play in the neuronal dysfunction and death that occur in neurodegenerative diseases that have tau pathology.

Animals↗

PubMed2004

Tau phosphorylation in neuronal cell function and dysfunction.

Tau is a group of neuronal microtubule-associated proteins that are formed by alternative mRNA splicing and accumulate in neurofibrillary tangles in Alzheimer's disease (AD) brain. Tau plays a key role in regulating microtubule dynamics, axonal transport and neurite outgrowth, and all these functions of tau are modulated by site-specific phosphorylation. There is significant evidence that a disruption of normal phosphorylation events results in tau dysfunction in neurodegenerative diseases, such as AD, and is a contributing factor to the pathogenic processes. Indeed, the abnormal tau phosphorylation that occurs in neurodegenerative conditions not only results in a toxic loss of function (e.g. decreased microtubule binding) but probably also a toxic gain of function (e.g. increased tau-tau interactions). Although tau is phosphorylated in vitro by numerous protein kinases, how many of these actually phosphorylate tau in vivo is unclear. Identification of the protein kinases that phosphorylate tau in vivo in both physiological and pathological processes could provide potential therapeutic targets for the treatment of AD and other neurodegenerative diseases in which there is tau pathology.

Alternative Splicing↗

PubMed2004

FRAT-2 preferentially increases glycogen synthase kinase 3 beta-mediated phosphorylation of primed sites, which results in enhanced tau phosphorylation.

Tau is a microtubule-associated protein found primarily in neurons, and its function is regulated by site-specific phosphorylation. Although it is well established that tau is phosphorylated at both primed and unprimed epitopes by glycogen synthase kinase 3 beta (GSK3 beta), how specific proteins that interact with GSK3 beta regulate tau phosphorylation has not been thoroughly examined. Members of the FRAT (frequently rearranged in advanced T-cell lymphoma) protein family have been shown to interact with GSK3 beta, and FRAT-1 has been shown to modulate the activity of GSK3 beta toward tau and other substrates. However, the effects of FRAT-2 on GSK3 beta activity and tau phosphorylation have not been examined. Therefore in this study the effects of FRAT-2 on GSK3 beta activity and tau phosphorylation were examined. In situ, FRAT-2 significantly increased GSK3 beta-mediated phosphorylation of tau at a primed epitope while not significantly affecting the phosphorylation of unprimed sites. Co-immunoprecipitation studies revealed that association of FRAT-2 with GSK3 beta resulted in a significant increase in phosphorylation of a primed substrate but did not alter phosphorylation of an unprimed substrate. Further, in vitro assays using recombinant proteins directly demonstrated that FRAT-2 enhances GSK3 beta-mediated phosphorylation of a primed substrate to a greater extent than an unprimed substrate. In addition, FRAT-2 is phosphorylated by GSK3 beta. This is the first demonstration of a protein differentially regulating the activity of GSK3 beta toward primed and unprimed epitopes.

Animals↗

PubMed2002

Axin negatively affects tau phosphorylation by glycogen synthase kinase 3beta.

Glycogen synthase kinase 3beta (GSK3beta) is an essential protein kinase that regulates numerous functions within the cell. One critically important substrate of GSK3beta is the microtubule-associated protein tau. Phosphorylation of tau by GSK3beta decreases tau-microtubule interactions. In addition to phosphorylating tau, GSK3beta is a downstream regulator of the wnt signaling pathway, which maintains the levels of beta-catenin. Axin plays a central role in regulating beta-catenin levels by bringing together GSK3beta and beta-catenin and facilitating the phosphorylation of beta-catenin, targeting it for ubiquitination and degradation by the proteasome. Although axin clearly facilitates the phosphorylation of beta-catenin, its effects on the phosphorylation of other GSK3beta substrates are unclear. Therefore in this study the effects of axin on GSK3beta-mediated tau phosphorylation were examined. The results clearly demonstrate that axin is a negative regulator of tau phosphorylation by GSK3beta. This negative regulation of GSK3beta-mediated tau phosphorylation is due to the fact that axin efficiently binds GSK3beta but not tau and thus sequesters GSK3beta away from tau, as an axin mutant that does not bind GSK3beta did not inhibit tau phosphorylation by GSK3beta. This is the first demonstration that axin negatively affects the phosphorylation of a GSK3beta substrate, and provides a novel mechanism by which tau phosphorylation and function can be regulated within the cell.

Axin Protein↗