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
Source: PubMed


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.

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    • "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.
    Scientific Reports 07/2014; 4:5715. DOI:10.1038/srep05715 · 5.58 Impact Factor
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    • "Because phosphorylation of Tau alters its association with the PM [57], it is not surprising that a dephosphorylated form of Tau would be more susceptible to secretion [14], [52], [58]-[60], thus leading to higher transfer of neuronal toxicity [61]. Our previous work indicated that secreted Tau is mainly dephosphorylated [41]. "
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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.
    PLoS ONE 06/2014; 9(6):e100760. DOI:10.1371/journal.pone.0100760 · 3.23 Impact Factor
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    • "Moreover, the dynamic translocation of tau between cytosolic and membrane compartments is regulated by Fyn, which phosphorylates Tyr 18 in tau [57] [65]. Increased tau phosphorylation has been shown to reduce its association with both Src homology 3 domains of membrane associated proteins, and neuronal membranes [54] [65], leading to the hypothesis that tau phosphorylation plays an integral role in tau localization to the plasma membrane in neurons. Nevertheless, the functional relevance of tau localization to both neuronal nuclei and membranes has yet to be fully elucidated. "
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    ABSTRACT: Tau has a well-established role as a microtubule-associated protein, in which it stabilizes the neuronal cytoskeleton. This function of tau is influenced by tau phosphorylation state, which is significantly increased in Alzheimer's disease and related tauopathies. Disruptions to the cytoskeleton in disease-affected neurons include reduced length and numbers of stable microtubules, and their diminished stability is associated with increased tau phosphorylation in disease. Tau is also localized in the nucleus and plasma membrane of neurons, where it could have roles in DNA repair and cell signaling. Most recently, potential roles for extracellular tau have been highlighted. The release of tau from neurons is a physiological process that can be regulated by neuronal activity and extracellular tau may play a role in inter-neuronal signaling. In addition, recent studies have suggested that the misfolding of tau in diseased brain leads to abnormal conformations of tau that can be taken up by neighboring neurons. Such a mechanism may be responsible for the apparent prion-like spreading of tau pathology through the brain, which occurs in parallel with clinical progression in the tauopathies. The relationship between tau localization in neurons, tau release, and tau uptake remains to be established, as does the function of extracellular tau. More research is needed to identify disease mechanisms that drive the release and propagation of pathogenic tau and to determine the impact of extracellular tau on cognitive decline in neurodegenerative disease.
    Journal of Alzheimer's disease: JAD 03/2014; 40. DOI:10.3233/JAD-132054 · 4.15 Impact Factor
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