Lost after translation: missorting of Tau protein and consequences for Alzheimer disease

Zempel, Hans; Mandelkow, Eckhard

doi:10.1016/j.tins.2014.08.004

Cited by 239 publications

(216 citation statements)

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“…Given the importance of MAPs for neuronal development and function, it is not surprising that many MAPs are associated with neurological and neurodegenerative diseases. For example, pathological aggregation of tau protein in the human brain leads to neurodegenerative diseases called tauopathies (Zempel and Mandelkow 2014). The best-known tauopathy is Alzheimer's disease, where tau protein is deposited within neurons in the form of neurofibrillary tangles (Avila et al 2004).…”

Section: Classical Mapsmentioning

confidence: 99%

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

2016

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Dendrites have a unique microtubule organization. In vertebrates, dendritic microtubules are organized in antiparallel bundles, oriented with their plus ends either pointing away or toward the soma. The mixed microtubule arrays control intracellular trafficking and local signaling pathways, and are essential for dendrite development and function. The organization of microtubule arrays largely depends on the combined function of different microtubule regulatory factors or generally named microtubule-associated proteins (MAPs). Classical MAPs, also called structural MAPs, were identified more than 20 years ago based on their ability to bind to and copurify with microtubules. Most classical MAPs bind along the microtubule lattice and regulate microtubule polymerization, bundling, and stabilization. Recent evidences suggest that classical MAPs also guide motor protein transport, interact with the actin cytoskeleton, and act in various neuronal signaling networks. Here, we give an overview of microtubule organization in dendrites and the role of classical MAPs in dendrite development, dendritic spine formation, and synaptic plasticity. IntroductionMicrotubules (MTs) are cytoskeletal structures that play essential roles in all eukaryotic cells. MTs are important not only during cell division but also in non-dividing cells, where they are critical structures in numerous cellular processes such as cell motility, migration, differentiation, intracellular transport and organelle positioning. MTs are composed of two proteins, α-and β-tubulin, that form heterodimers and organize themselves in a head-to-tail manner. MTs are dynamic and they can rapidly switch between cycles of growth and shrinkage. This MT

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Section: Classical Mapsmentioning

confidence: 99%

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

2016

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“…Under normal conditions, tau has a polarized distribution in the axon, while diseased neurons exhibit extensive accumulation of tau, both soluble and inclusions, within the somatodendritic compartment. Somatodendritic tau has been demonstrated to result from tau mutation, hyperphosphorylation, and overexpression [202]. A major source of tau toxicity in neurons seems to be through mediating Aβ neurotoxicity in dendrites.…”

Section: Tau In Diseasementioning

confidence: 99%

“…10,000 contiguous pixels was chosen as the cutoff between intact and disrupted tau for all subsequent assays. within the somatodendritic compartment [202]. This redistribution of tau is associated with a number of toxic effects, including glutamate toxicity resulting from tau interaction with the kinase, fyn, and spastin cleavage of microtubules (discussed in chapter 1-11.…”

Section: Robust Disruption Of Fast Axonal Transport Disruption By Extmentioning

confidence: 99%

“…Accumulation of somatodendritic tau has been shown to result from tau mutation, hyperphosphorylation and over-expression of tau [202]. Studies presented in chapter 3 demonstrate that exposure of primary neurons to extra-cellular tau oligomers also resulted in considerable accumulation of somatodendritic tau.…”

Section: Robust Disruption Of Fast Axonal Transport Disruption By Extmentioning

confidence: 99%

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Extracellular Tau Oligomers Induce Disruption of Endogenous Tau Distribution, Invasion of Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction

Swanson

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Insoluble hyperphosphylated aggregates of the microtubule-associated protein tau define a subset of neurodegenerative disorders known as tauopathies, of which Alzheimer's Disease is the most prevalent. Extracellular tau can induce the accumulation and aggregation of intracellular tau, and tau pathology can be transmitted along neural networks, in a manner that recapitulates the temporal spread of pathology observed

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“…When axons emerge and neurons become polarized, Tau becomes enriched in axons. In mammalian neurons, this axonal sorting takes place within 1-2 weeks [73]. In mature neurons, under physiological conditions, the majority of Tau is localized to the axon, whereas MAP2, another member of the MAP family, is mainly localized to the dendrite.…”

Section: Introductionmentioning

confidence: 99%

The molecular mechanism of the Tau-Fyn interaction and dendritic targeting in neurons

Xia¹

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Alzheimer's disease (AD) is the most common form of neurodegenerative disorder that progresses with aging. The AD brain is characterized by a massive loss of neurons and synapses. Two key hallmarks of AD are the aggregation of the amyloid-β (Aβ) peptide as plaques and of the microtubule-associated protein Tau as neurofibrillary tangles. Under physiological conditions, Tau is mainly localized to the axon of neurons, with low levels of expression found in dendrites and spines. Under disease conditions, Tau is hyperphosphorylated and accumulates in the somatodendritic domain of neurons including spines. Recent data suggest that dendritic spine-targeted Tau disrupts synaptic function and causes synaptic loss long before neurofibrillary tangle formation and neuronal loss occurs.Fyn is a non-receptor tyrosine kinase that mainly targets to the postsynaptic membrane in spines. Fyn interacts with and phosphorylates Tau and this interaction has a critical role in mediating Aβ toxicity. Understanding how Tau and Fyn are targeted to the dendritic spine and how their trafficking and interaction is regulated under both physiological and pathological conditions is critical for understanding how AD is initiated in the synapse and for developing novel therapeutic approaches to delay, halt or treat AD.Fyn phosphorylates Tau mainly at Tyr18; however, it is unclear how tyrosine phosphorylation of Tau by Fyn affects serine/ threonine phosphorylation. In the first part of my thesis, I have generated a transgenic animal model that expresses constitutively active Fyn and studied the functional consequence of Fyn activation, especially for Tau. We found that FynCA animals showed premature lethality and hyperactive phenotypes reflecting the synaptic over-excitation by Fyn as expected. A biochemical analysis of isolated synaptosomes revealed increased levels of the NMDA receptor subunit NR2b phosphorylated at residue Y1472, and of Tau phosphorylated at the 12E8 phosphoepitope S262/S356. Besides, Tau phosphorylation at the AT8 epitope S202/T205 was strongly increased in FynCA mice as revealed by both immunohistochemistry and Western blot analysis. Our results indicate that an increased tyrosine kinase activity of Fyn has a role in serine/threonine-directed phosphorylation of Tau, which may contribute to the tauopathy in AD. 3 Under physiological conditions, low levels of Tau are targeted to dendritic spines in a process that is regulated by synaptic activity and Aβ levels. It has also been reported that hyperphosphorylated Tau mislocalizes into the spine, although it is not clear what kind of phosphorylation is required. In order to understand how Tau enters the spines and the role of Fyn in dendritic spine targeting of Tau, we performed an extensive mutagenesis study by overexpressing different mutant forms of Tau in cultured wildtype or FynKO neurons.Our results revealed that the spine localization of Tau is facilitated by deletion of the microtubule-binding repeat domain. Distinct pseudophosphorylation at AD related sites AT180(...

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Lost after translation: missorting of Tau protein and consequences for Alzheimer disease

Cited by 239 publications

References 132 publications

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

Extracellular Tau Oligomers Induce Disruption of Endogenous Tau Distribution, Invasion of Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction

The molecular mechanism of the Tau-Fyn interaction and dendritic targeting in neurons

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