Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells

Gómez-Ramos, Alberto; Dı́az-Hernández, Miguel; Rubio, Alicia; Miras-Portugal, Marı́a Teresa; Ávila, Jesús

doi:10.1016/j.mcn.2007.12.010

Cited by 209 publications

(196 citation statements)

References 33 publications

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“…Another possibility is that the Tau protein itself serves as the agent of trans-cellular propagation. For example, it has been shown that extracellular Tau is toxic to cultured neuronal cells (13,14). This is consistent with the observation that immunotherapy against Tau reduces pathology in a mouse model (15).…”

supporting

confidence: 79%

Propagation of Tau Misfolding from the Outside to the Inside of a Cell

Frost

Jacks

Diamond

2009

Journal of Biological Chemistry

1,069

1,023

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supporting

confidence: 79%

Propagation of Tau Misfolding from the Outside to the Inside of a Cell

Frost

Jacks

Diamond

2009

Journal of Biological Chemistry

1,069

1,023

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“…5). The specific phosphorylation of MAP2c Ser-435 and its physicochemical consequences are particularly interesting because this region is responsible for the ability of Tau to act as a muscarinic agonist (52).…”

Section: Phosphorylation Of Map2c and Interaction With 14-3-3mentioning

confidence: 99%

Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau

Jansen

Melková

Trošanová

et al. 2017

Journal of Biological Chemistry

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Edited by Norma AllewellMicrotubule-associated protein 2c (MAP2c) is involved in neuronal development and is less characterized than its homolog Tau, which has various roles in neurodegeneration. Using NMR methods providing single-residue resolution and quantitative comparison, we investigated molecular interactions important for the regulatory roles of MAP2c in microtubule dynamics. We found that MAP2c and Tau significantly differ in the position and kinetics of sites that are phosphorylated by cAMP-dependent protein kinase (PKA), even in highly homologous regions. We determined the binding sites of unphosphorylated and phosphorylated MAP2c responsible for interactions with the regulatory protein 14-3-3 . Differences in phosphorylation and in charge distribution between MAP2c and Tau suggested that both MAP2c and Tau respond to the same signal (phosphorylation by PKA) but have different downstream effects, indicating a signaling branch point for controlling microtubule stability. Although the interactions of phosphorylated Tau with 14-3-3 are supposed to be a major factor in microtubule destabilization, the binding of 14-3-3 to MAP2c enhanced by PKA-mediated phosphorylation is likely to influence microtubule-MAP2c binding much less, in agreement with the results of our tubulin co-sedimentation measurements. The specific location of the major MAP2c phosphorylation site in a region homologous to the muscarinic receptor-binding site of Tau suggests that MAP2c also may regulate processes other than microtubule dynamics.Cytoskeletal microtubule-associated proteins (MAPs) 3 are proteins of critical importance for regulating the stability and dynamics of microtubules (1). MAP2 and Tau represent MAP subfamilies expressed in neurons; MAP2 is localized in dendrites, whereas Tau is found mainly in axons (2). Tau and MAP2 belong to the class of intrinsically disordered proteins (IDPs), which lack a unique structure and which exist in multiple, quickly interconverting conformations (3-7). NMR is the method of choice for structural investigation of this type of protein. Tau and MAP2 differ in their N-terminal projection domains, which contain acidic and proline-rich subdomains, whereas the C-terminal parts, containing the microtubulebinding domain (MTBD) and the C-terminal region, are homologous (8). Tau is expressed in several splice variants. The human brain isoforms differ in the number of microtubulebinding regions (MTBRs) in the C-terminal portion and in the presence of two inserts near the N terminus. For the sake of simplicity, only the 441-residue variant lacking exons 6, 8, and 10 (9) is discussed in this paper. This variant has been studied in detail and was shown to form paired helical filaments and neurofibillary tangles in brains of patients suffering from Alzheimer's disease (10). The MAP2 family is composed of two high-molecular-weight proteins, MAP2a and MAP2b, each consisting of 1830 amino acids, and two low-molecular-weight proteins, MAP2c and MAP2d, consisting of 467 and 498 amino acids, respectively. The ...

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“…Interestingly, transgenic mouse models suggest that neuronal loss and memory impairment are associated with the presence of soluble tau protein [75] (tau oligomers). Studies on cell viability have shown that misfolding of tau leads to the aggregation of tau and the appearance of toxic tau species in the extracellular space [81,82]. The endogenous intracellular tau may be released as aggregates to the extracellular space upon neuron degeneration [81].…”

Section: Ad Pathogenesis: Tau-dependent Mechanisms and Synaptic Dysfumentioning

confidence: 99%

“…The endogenous intracellular tau may be released as aggregates to the extracellular space upon neuron degeneration [81]. Extracellular tau could be toxic by increasing intracellular calcium into neighboring neurons [82]. The presence of extracellular tau can be due to other causes, for example exocytosis; the N-terminal region of tau seems to be required for its secretion [83].…”

Section: Ad Pathogenesis: Tau-dependent Mechanisms and Synaptic Dysfumentioning

confidence: 99%