Dynamic association of tau with neuronal membranes is regulated by phosphorylation
King's College London, MRC Centre for Neurodegeneration Research, Department of Neuroscience, Institute of Psychiatry, London, UK. Neurobiology of aging
(Impact Factor: 5.01).
03/2011; 33(2):431.e27-38. DOI: 10.1016/j.neurobiolaging.2011.01.005
Tau is an abundant cytosolic protein which regulates cytoskeletal stability by associating with microtubules in a phosphorylation-dependent manner. We have found a significant proportion of tau is located in the membrane fraction of rat cortical neurons and is dephosphorylated, at least at Tau-1 (Ser199/Ser202), AT8 (Ser199/Ser202/Thr205) and PHF-1 (Ser396/Ser404) epitopes. Inhibition of tau kinases casein kinase 1 (CK1) or glycogen synthase kinase-3 decreased tau phosphorylation and significantly increased amounts of tau in the membrane fraction. Mutation of serine/threonine residues to glutamate to mimic phosphorylation in the N-terminal, but not C-terminal, region of tau prevented its membrane localization in transfected cells, demonstrating that the phosphorylation state of tau directly impacts its localization. Inhibiting CK1 in neurons lacking the tyrosine kinase fyn also induced tau dephosphorylation but did not affect its membrane association. Furthermore, inhibition of CK1 increased binding of neuronal tau to the fyn-SH3 domain. We conclude that trafficking of tau between the cytosol and the neuronal membrane is dynamically regulated by tau phosphorylation through a mechanism dependent on fyn expression.
Available from: Jean-Pierre Brion
- "Mouse cortical tissue was disrupted in hypotonic buffer (10-mM sodium bicarbonate containing 20-mg/mL deoxyribonuclease I (DNase I), 1-mM sodium orthovanadate, and Complete protease inhibitor cocktail) by sonication using 5 strokes with probe sonicator on ice. Samples were then processed as described previously (Pooler et al., 2012). Briefly, lysates were centrifuged at 720 g for 5 minutes at 4 C. "
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ABSTRACT: Hyperphosphorylation and fibrillar aggregation of the microtubule-associated protein tau are key features of Alzheimer’s disease and other tauopathies. To investigate the involvement of tau phosphorylation in the pathological process we generated a pair of complementary phosphomutant tau knockin mouse lines. One exclusively expresses phosphomimetic tau with 18 glutamate substitutions at serine/threonine residues in the proline-rich and first microtubule-binding domains to model hyperphosphorylation, whilst its phosphodefective counterpart has matched alanine substitutions. Consistent with expected effects of genuine phosphorylation, association of the phosphomimetic tau with microtubules and neuronal membranes is severely disrupted in vivo, whereas the phosphodefective mutations have more limited or no effect. Surprisingly, however, age-related mislocalization of tau is evident in both lines, although redistribution appears more widespread and more pronounced in the phosphomimetic tau knockin. Despite these changes, we found no biochemical or immunohistological evidence of pathological tau aggregation in mice of either line up to at least two years of age. These findings raise important questions about the role of tau phosphorylation in driving pathology in human tauopathies.
Available from: Nicole Leclerc
- "Several unconventional secretory pathways exist and therefore different tau species might have access to distinct pathways8. Furthermore, several studies including ours have reported that two pools of tau, a cytosolic and membranous one are present in neurons44454647. Each of these pools could have access to different secretory pathways in starved neurons. "
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ABSTRACT: Recent studies have demonstrated that human tau can be secreted by neurons and non-neuronal cells, an event linked to the propagation of tau pathology in the brain. In the present study, we confirmed that under physiological conditions, one tau-positive band was detected in the culture medium with an anti-tau antibody recognizing total tau and the Tau-1 antibody directed against unphosphorylated tau. We then examined whether tau secretion was modified upon insults. Tau secretion was increased by starvation [Earle's Balanced Salt Solution (EBSS)], inhibition of lysosomal function (leupeptin) and when both of these conditions were superimposed, this combined treatment having the most important effects on tau secretion. Interestingly, the pattern of tau secretion was distinct from that of control neurons when neurons were treated either with EBSS alone or EBSS + leupeptin. In these conditions, three tau-positive bands were detected in the culture medium. Two of these three bands were immunoreactive to Tau-1 antibody revealing that at least two tau species were released upon these treatments. Collectively, our results indicate that insults such as nutrient deprivation and lysosomal dysfunction observed in neurodegenerative diseases could result in an increase of tau secretion and propagation of tau pathology in the brain.
Available from: Philippe Hantraye
- "Because phosphorylation of Tau alters its association with the PM , it is not surprising that a dephosphorylated form of Tau would be more susceptible to secretion , , -, thus leading to higher transfer of neuronal toxicity . Our previous work indicated that secreted Tau is mainly dephosphorylated . "
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ABSTRACT: Tau is a microtubule-associated protein that aggregates in neurodegenerative disorders known as tauopathies. Recently, studies have suggested that Tau may be secreted and play a role in neural network signalling. However, once deregulated, secreted Tau may also participate in the spreading of Tau pathology in hierarchical pathways of neurodegeneration. The mechanisms underlying neuron-to-neuron Tau transfer are still unknown; given the known role of extra-cellular vesicles in cell-to-cell communication, we wondered whether these vesicles could carry secreted Tau. We found, among vesicles, that Tau is predominately secreted in ectosomes, which are plasma membrane-originating vesicles, and when it accumulates, the exosomal pathway is activated.
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