Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau

Fontela, Yunior Cabrales; Kadavath, Harindranath; Biernat, Jacek; Riedel, Dietmar; Mandelkow, Eckhard; Zweckstetter, Markus

doi:10.1038/s41467-017-02230-8

Cited by 112 publications

(81 citation statements)

References 80 publications

(109 reference statements)

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“…Although full-length tau isoforms are generally considered highly soluble proteins free of structure, recently solved atomic resolution structures of tau microtubule-binding domain in complex with cytoskeleton proteins 29,30 suggest that tau adopts particular tertiary structures upon interacting with its binding partners in biological systems. Under non-denaturing experimental conditions like simoa and immunoprecipitation, it is conceivable www.nature.com/scientificreports www.nature.com/scientificreports/ that certain tau epitopes targeted by antibodies were inaccessible to the capture/detection reagents, resulting in inaccurate quantification and discrepant outcomes between different types of assays.…”

Section: Discussionmentioning

confidence: 99%

A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals

Liu

Smith

Montonye

et al. 2020

Sci Rep

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Neurofibrillary tangles are a pathological hallmark of Alzheimer's disease, and their levels correlate with the severity of cognitive dysfunction in humans. However, experimental evidence suggests that soluble tau species cause cognitive deficits and memory impairment. Our recent study suggests that caspase-2 (Casp2)-catalyzed tau cleavage at aspartate 314 mediates synaptic dysfunction and memory impairment in mouse and cellular models of neurodegenerative disorders. Δtau314, the C-terminallytruncated cleavage products, are soluble and present in human brain. In addition, levels of Δtau314 proteins are elevated in the brain of the cognitively impaired individuals compared to the cognitively normal individuals, indicating a possible role for Δtau314 proteins in cognitive deterioration. Here we show that (1) Δtau314 proteins are present in the inferior temporal gyrus of human brains; (2) Δtau314 proteins are generated from all six tau splicing isoforms, (3) levels of both Casp2 and Δtau314 proteins are elevated in cognitively impaired individuals compared to cognitively normal individuals, and (4) levels of Δtau314 proteins show a modest predictive value for dementia. These findings advance our understanding of the characteristics of Δtau314 proteins and their relevance to cognitive dysfunction and shed light on the contribution of Casp2-mediated Δtau314 production to cognitive deterioration.Tau is a soluble and unstructured protein, is enriched in neurons of the central nervous system (CNS), and plays an essential role in the formation and stabilization of microtubules to maintain normal neuronal structure and function 1,2 . In the human CNS, six isoforms of tau are generated by alternative splicing of exons 2, 3, or 10 of mRNA 3,4 . Tau is subjected to more than ten types of post-translational modifications (PTMs); under pathological conditions, the coordinated actions of multiple tau PTMs result in its dissociation from microtubules and intra-cellular aggregation to form neurofibrillary tangles (NFTs), a pathological hallmark of Alzheimer's disease (AD) (for review, see 5 ). As the burden of NFTs in a variety of brain regions correlate well with the severity of cognitive deficits of AD patients (for example, see 6-10 ), NFTs were assumed to be one of the major drivers of cognitive impairment. However, Gomez-Isla and colleagues observed that in the brain of individuals with AD, both the amount of neuron loss and the amount of NFTs in the disease-affected superior temporal sulcus correlate with the duration and severity of cognitive dysfunction, but the former exceeds the latter more than 7-fold. This suggests that neuronal loss, rather than NFTs, contributes directly to cognitive dysfunction in AD 11 . Further, several studies using tau transgenic mouse models have shown that synaptic function impairment and cognitive deficits

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Section: Discussionmentioning

confidence: 99%

A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals

Liu

Smith

Montonye

et al. 2020

Sci Rep

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“…Should a reduction in pS214‐tau density signal a loss‐of‐function event, its absence from the subsynaptic domain may be particularly important to synaptic stability mechanisms. Specifically, tau within the subsynaptic domain is both strategically positioned to directly bind the actin cytoskeleton, and to participate in intracellular signaling cascades critical for actin remodeling, for example, the MAPK pathway (Cabrales Fontela et al, ; Frandemiche et al, ; He et al, ; Leugers, Koh, Hong, & Lee, ; Yamauchi & Purich, ). Notably, the interaction between tau and actin leads to accumulation of actin within mouse cortical neuron synapses (Frandemiche et al, ).…”

Section: Discussionmentioning

confidence: 99%

Synaptic distributions of pS214‐tau in rhesus monkey prefrontal cortex are associated with spine density, but not with cognitive decline

Crimins

Puri

Calakos

et al. 2018

J of Comparative Neurology

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Female rhesus monkeys and women are subject to age‐ and menopause‐related deficits in working memory, an executive function mediated by the dorsolateral prefrontal cortex (dlPFC). Long‐term cyclic administration of 17β‐estradiol improves working memory, and restores highly plastic axospinous synapses within layer III dlPFC of aged ovariectomized monkeys. In this study, we tested the hypothesis that synaptic distributions of tau protein phosphorylated at serine 214 (pS214‐tau) are altered with age or estradiol treatment, and couple to working memory performance. First, ovariectormized young and aged monkeys received vehicle or estradiol treatment, and were tested on the delayed response (DR) test of working memory. Serial section electron microscopic immunocytochemistry was then performed to quantitatively assess the subcellular synaptic distributions of pS214‐tau. Overall, the majority of synapses contained pS214‐tau immunogold particles, which were predominantly localized to the cytoplasm of axon terminals. pS214‐tau was also abundant within synaptic and cytoplasmic domains of dendritic spines. The density of pS214‐tau immunogold within the active zone, cytoplasmic, and plasmalemmal domains of axon terminals, and subjacent to the postsynaptic density within the subsynaptic domains of dendritic spines, were each reduced with age. None of the variables examined were directly linked to cognitive status, but a high density of pS214‐tau immunogold particles within presynaptic cytoplasmic and plasmalemmal domains, and within postsynaptic subsynaptic and plasmalemmal domains, accompanied high synapse density. Together, these data support a possible physiological, rather than pathological, role for pS214‐tau in the modulation of synaptic morphology in monkey dlPFC.

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“…Based on our discovery of a close spatial and temporal relationship between lysosome accumulations and disruption of the actin/spectin and microtubule cytoskeleton in JIP3 KO neurons, we wondered whether these findings could have any relevance for microtubule related aspects of Alzheimer's disease brain pathology. A hallmark of Alzheimer disease is the presence of hyperphosphorylated tau (De Strooper and Karran, 2016), a microtubule-associated protein that links microtubules to actin (Cabrales Fontela et al, 2017). Thus, we measured total tau levels as well as the phosphorylation states of sites (Thr181, Ser202/205, Ser396) that exhibit increased phosphorylation in Alzheimer disease brains.…”

Section: Axonal Swellings Are Highly Dynamicmentioning

confidence: 99%

JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton

Rafiq

Lyons

Gowrishankar

et al. 2020

Preprint

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Lysosome axonal transport is important for the clearance of cargoes sequestered by the endocytic and autophagic pathways. Building on observations that mutations in the JIP3 (MAPK8IP3) gene result in lysosome-filled axonal swellings, we analyzed the impact of JIP3 depletion on the cytoskeleton of human neurons. Dynamic focal lysosome accumulations were accompanied by disruption of the axonal periodic scaffold (spectrin, F-actin and myosin II) throughout each affected axon. Additionally, axonal microtubule organization was locally disrupted at each lysosome-filled swelling.This axonal microtubule disorganization in JIP3 KO neurons was accompanied by increased tau abundance and phosphorylation. These results indicate that transport of axonal lysosomes is integrated into a much larger network that is required for the maintenance of the axonal cytoskeleton. These findings have potential relevance to human neurological disease arising from JIP3 mutations as well as for neurodegenerative tauopathies such as Alzheimer's disease.

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Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau

Cited by 112 publications

References 80 publications

A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals

A soluble truncated tau species related to cognitive dysfunction is elevated in the brain of cognitively impaired human individuals

Synaptic distributions of pS214‐tau in rhesus monkey prefrontal cortex are associated with spine density, but not with cognitive decline

JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton

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