Mutations in tau reduce its microtubule binding properties in intact cells and affect its phosphorylation

Dayanandan, R; Slegtenhorst, Marjon van; Mack, Till G. A.; Ko, Li Wen; Yen, Shu Hui; Leroy, Karelle; Brion, Jean Pierre; Anderton, Brian H.; Hutton, Michael; Lovestone, Simon

doi:10.1016/s0014-5793(99)00222-7

Cited by 197 publications

(166 citation statements)

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“…DISCUSSION The purpose of this study was to establish a cellular model system in which R06W mutant tau exhibited characteristics of tau with the R406W mutation in the human disease state. The results presented in this study clearly demonstrate that when R406W mutant tau is stably expressed in mouse cortical cells it is hyperphosphorylated and thus reproduces a key biochemical property of R406W mutant tau from FTDP-17 cases (30, 31), unlike previous cell models of the R406W FTDP-17 mutation (22,23,34). Furthermore, the microtubule-binding capacity of R406W mutant tau expressed in cortical cells is impaired, but this loss of microtubule binding was reversed or "rescued" by dephosphorylating the tau.…”

Section: Cellular Localization Of Wild Type and Mutant R406wsupporting

confidence: 62%

“…Using this cell model the effects of wild type and R406W mutant tau on cell morphology were examined, and the effects of the R406W mutation on tau localization and interactions with the cytoskeleton and microtubules were evaluated further. Previous cell models in which R406W mutant tau was expressed (20,22,23) were unable to reproduce the increased tau phosphorylation that occurs in FTDP-17 brains with this mutation (30,31). However, in this study we show that in stably transfected cortical cells, mutant R406W tau is more highly phosphorylated than wild type tau, and therefore this cell model provides an appropriate system to examine the effects of this mutation on tau function.…”

mentioning

confidence: 59%

“…Previously reported cell models of the R406W mutation have not been successful at reproducing the increased phosphorylation observed in vivo (22,23,34,55). A possible explanation for this could simply be that it is due to using non-neuronal cells such as Chinese hamster ovary and COS-1 cells (22)(23)(24)34).…”

Section: Cellular Localization Of Wild Type and Mutant R406wmentioning

confidence: 97%

“…However, these data are not unequivocal because identical in vitro assays have given differing results (16,19) and there is some discussion as to the extent to which the FTDP-17 missense mutations affect tau-microtubule interactions (18,20). The effects of the FTDP-17 mutations on the ability of tau to interact with microtubules and affect microtubule function in situ have also been examined with variable outcomes being reported (21)(22)(23). It should be noted that the majority of these previous studies were carried out using either cell-free systems or non-neuronal cells that had been transiently transfected with wild type or FTDP-17 mutant tau constructs (16, 19 -24).…”

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confidence: 99%

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Mutant (R406W) Human Tau Is Hyperphosphorylated and Does Not Efficiently Bind Microtubules in a Neuronal Cortical Cell Model

Krishnamurthy

Johnson

2004

Journal of Biological Chemistry

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Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative disorder caused by mutations in the gene that encodes for tau, a microtubule-binding protein. Neuropathologically the disease is characterized by extensive neuronal loss in the frontal and temporal lobes and the filamentous accumulation of hyperphosphorylated tau. The R406W missense mutation was originally described in an American and a Dutch family. Although R406W tau is hyperphosphorylated in FTDP-17 cases, R406W tau expressed in cell model systems has not shown increased phosphorylation. The purpose of this study was to establish a neuronal model system in which the phosphorylation of R406W tau is increased and thus more representative of the in vivo situation. To accomplish this goal immortalized mouse cortical cells that express low levels of endogenous tau were stably transfected with human wild type or R406W tau. In this neuronal model R406W tau was more highly phosphorylated at numerous epitopes and showed decreased microtubule binding compared with wild type tau, an effect that could be reversed by dephosphorylation. In addition the expression of R406W tau in the cortical cells resulted in increased cell death as compared with wild type tau-expressing cells when the cells were exposed to an apoptotic stressor. These results indicate that in an appropriate cellular context R406W tau is hyperphosphorylated, which leads to decreased microtubule binding. Furthermore, expression of R406W tau sensitized cells to apoptotic stress, which may contribute to the neuronal cell loss that occurs in this FTDP-17 tauopathy.Frontotemporal dementia (FTD) 1 refers to a group of neurological disorders that are characterized clinically by progressive behavioral changes and neuropathologically by neuronal loss in the frontal and temporal lobes and the presence of filamentous deposits of abnormally hyperphosphorylated tau protein in neurons and/or glial cells (1-4). FTDs occur mainly as sporadic cases but also as familial forms with an autosomal dominant mode of inheritance and age-dependent penetrance (1). In 1998 it was demonstrated that several familial FTDs were due to mutations in the tau gene and have been referred to as frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) (5-7). Since these initial discoveries, additional tau mutations have been described in frontotemporal dementia families, and presently over 25 mutations in the tau gene have been identified (8, 9). They include missense mutations in coding regions, amino acid deletions, and intronic mutations in the region following exon 10. The mutations may be divided into two main groups, those that affect alternative splicing of exon 10, leading to changes in the ratio of tau mRNAs with or without exon 10, and thus the proportion of tau with three microtubule binding repeats versus tau with four microtubule binding repeats, and missense mutations.Tau is a microtubule-associated protein that facilitates microtubule assembly an...

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Section: Cellular Localization Of Wild Type and Mutant R406wsupporting

confidence: 62%

mentioning

confidence: 59%

Section: Cellular Localization Of Wild Type and Mutant R406wmentioning

confidence: 97%

mentioning

confidence: 99%

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Mutant (R406W) Human Tau Is Hyperphosphorylated and Does Not Efficiently Bind Microtubules in a Neuronal Cortical Cell Model

Krishnamurthy

Johnson

2004

Journal of Biological Chemistry

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“…For example, it is known that 4-R tau binds MTs more avidly than 3-R tau (Panda et al 2003), and thus FTDP-17 mutations that result in increased 4-R tau because of altered splicing of exon 10 (Hong et al 1998) might lead to an overstabilization of MTs with resulting axonal dysfunction. Conversely, FTDP-17 mutations within the MT-binding domains of tau generally reduce the binding of tau to MTs (Hasegawa et al 1998;Hong et al 1998;Dayanandan et al 1999), perhaps leading to a destabilization of MTs. In addition, mutations that reduce tau binding to MTs could increase the concentration of unbound tau and thus promote the formation of tau multimers and fibrils that have been proposed to elicit a direct toxic effect on neurons.…”

Section: Introduction To Tau Pathology and Geneticsmentioning

confidence: 99%

Developing Therapeutic Approaches to Tau, Selected Kinases, and Related Neuronal Protein Targets

Lee¹,

Brunden²,

Hutton³

et al. 2011

Cold Spring Harbor Perspectives in Medicine

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Missense point mutations of tau to segregate with FTDP-17 exhibit site-specific effects on microtubule structure in COS cells: A novel action of R406W mutation

2000

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Missense and splicing point mutations have been found in the tau gene in families with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Of these mutations, we examined four exonic missense point mutations (G272V, P301L, V337M and R406W) in 3-repeat or 4-repeat tau isoform on the transfection experiment. The effects of two mutations (G272V or P301L) on microtubules were subtle whereas those of two other mutations (V337M or R406W) were dramatically significant when these two mutations were constructed into 3-repeat tau but not into 4-repeat tau. The R406W mutation induced an alternation of microtubules to form dotted or fragmented forms retaining colocalization of tau with tubulin whereas the V337M mutation predominantly disrupted microtubule networks and diminished colocalization of tau and tubulin. The effect of the mutations on microtubules were thus site-dependent and isoform-dependent. Tau with R406W mutation was found to be colocalized with tubulin without filamentous structures on confocal views, suggesting that the carboxyl region of tau played a different role from tubulin-binding domain on microtubule assemble. Another abnormal property was identified in tau with R406W mutation that failed to suffer phosphorylation. Thus, diverse effects of tau mutations on microtubules may explain the various clinicopathologies of FTDP-17 and related tauopathies.

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Mutations in tau reduce its microtubule binding properties in intact cells and affect its phosphorylation

Cited by 197 publications

References 26 publications

Mutant (R406W) Human Tau Is Hyperphosphorylated and Does Not Efficiently Bind Microtubules in a Neuronal Cortical Cell Model

Mutant (R406W) Human Tau Is Hyperphosphorylated and Does Not Efficiently Bind Microtubules in a Neuronal Cortical Cell Model

Developing Therapeutic Approaches to Tau, Selected Kinases, and Related Neuronal Protein Targets

Missense point mutations of tau to segregate with FTDP-17 exhibit site-specific effects on microtubule structure in COS cells: A novel action of R406W mutation

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