Missense tau mutations identified in FTDP-17 have a small effect on tau–microtubule interactions

DeTure, Michael; Ko, Li Wen; Yen, Shu‐Hui; Nacharaju, Parimala; Easson, Colin; Lewis, Jada; Slegtenhorst, Marjon van; Hutton, Michael; Yen, Shu Hui

doi:10.1016/s0006-8993(99)02124-1

Cited by 78 publications

(60 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

“…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). However, R406W mutant tau also was in a lower phosphorylation state than wild type tau when expressed in more neurallike cell systems such as neuroglioma cells (55) and neuroblastoma cells (20). Interestingly, the one reported R406W mutant transgenic mouse model did show evidence of hyperphosphorylated tau inclusions in forebrain neurons (56).…”

Section: Cellular Localization Of Wild Type and Mutant R406wmentioning

confidence: 99%

“…The mutations can also impair the ability of tau to stimulate the formation of microtubules by increasing the lag time and reducing the rate of polymerization (16,17,19). 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).…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

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...

show abstract

mentioning

confidence: 59%

Section: Cellular Localization Of Wild Type and Mutant R406wmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

show abstract

“…19-21, 34, 38, and 39). The initial in vitro analyses of point-mutated tau proteins revealed relatively subtle reductions in MT-binding and assembly activities (5,(40)(41)(42). Many point-mutated proteins also increase tau fiber formation activity in vitro (29,41,43,44).…”

Section: Mechanistic Implications For Tau-mediated Neuronal Cell Deatmentioning

confidence: 99%

Differential regulation of microtubule dynamics by three- and four-repeat tau: Implications for the onset of neurodegenerative disease

Panda

Samuel

Massie

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

240

243

View full text Add to dashboard Cite

The microtubule (MT)-associated protein tau is important in neuronal development and in Alzheimer's and other neurodegenerative diseases. Genetic analyses have established a cause-and-effect relationship between tau dysfunction͞misregulation and neuronal cell death and dementia in frontotemporal dementia and parkinsonism associated with chromosome 17; several mutations causing this dementia lead to increased ratios of four-repeat (4R) to three-repeat (3R) wild-type tau, and an attractive hypothesis is that the abnormally high ratio of 4R to 3R tau might lead to neuronal cell death by altering normal tau functions in adult neurons. Thus, we tested whether 3R and 4R tau might differentially modulate the dynamic instability of MTs in vitro using video microscopy. Although both isoforms promoted MT polymerization and decreased the tubulin critical subunit concentration to approximately similar extents, 4R tau stabilized MTs significantly more strongly that 3R tau. For example, 4R tau suppressed the shortening rate, whereas 3R tau had little or no detectable effect. Similarly, 3R tau had no effect on the length shortened during a shortening event, whereas 4R tau strongly reduced this parameter. Further, when MTs were diluted into buffer containing 4R tau, the MTs were stabilized and shortened slowly. In contrast, when diluted into 3R tau, the MTs were unstable and shortened rapidly. Thus, 4R tau stabilizes MTs differently and significantly more strongly than 3R tau. We suggest a ''dosage effect'' or haploinsufficiency model in which both tau alleles must be active and properly regulated to produce appropriate amounts of each tau isoform to maintain MT dynamics within a tolerable window of activity.M any neurodegenerative diseases exhibit abnormal pathological fibers composed primarily of the microtubule (MT)-associated protein, tau (for a recent review, see ref. 1). These disorders, termed ''tauopathies,'' include Alzheimer's disease, frontotemporal dementia and parkinsonism associated with chromosome 17 (FTDP-17), Pick's disease, and progressive supranuclear palsy. In 1998, several groups reported a direct genetic linkage between mutations in the tau gene and FTDP-17 (2-5). Although some tau mutations are structural and others are regulatory, all exhibit dominant phenotypes. Thus, both dysfunction and misregulation of tau are causally related to neuronal cell death, neurodegenerative disease, and dementia.Tau is normally present predominantly in the cell bodies and axons of neuronal cells and is necessary for the establishment of neuronal cell polarity and axon outgrowth, axonal transport, and maintenance of axonal morphology (6-10). Tau is also expressed in glial cells (11). Mechanistically, tau stimulates MT polymerization, stabilizes MTs, and suppresses MT dynamics (12-15). Because MT dynamics must be tightly regulated for cells to function and remain viable (e.g., ref. 16), it follows that the action of tau must also be finely regulated.Although there is only a single tau gene, alternative splicing of tau mRNA p...

show abstract

“…24). Tau molecules containing these mutations generally possess deficits in the ability to bind and promote assembly of microtubules in vitro (10,(33)(34)(35)(36). Mutant Tau molecules also often exhibit an increased propensity to form abnormal Tau fibers in vitro (37)(38)(39)(40)(41)(42).…”

mentioning

confidence: 99%

FTDP-17 Mutations in Tau Alter the Regulation of Microtubule Dynamics

LeBoeuf

Levy

Gaylord

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Mutations affecting either the structure or regulation of the microtubule-associated protein Tau cause neuronal cell death and dementia. However, the molecular mechanisms mediating these deleterious effects remain unclear. Among the most characterized activities of Tau is the ability to regulate microtubule dynamics, known to be essential for proper cell function and viability. Here we have tested the hypothesis that Tau mutations causing neurodegeneration also alter the ability of Tau to regulate the dynamic instability behaviors of microtubules. Using in vitro microtubule dynamics assays to assess average microtubule growth rates, microtubule growth rate distributions, and catastrophe frequencies, we found that all tested mutants possessing amino acid substitutions or deletions mapping to either the repeat or interrepeat regions of Tau do indeed compromise its ability to regulate microtubule dynamics. Further mutational analyses suggest a novel mechanism of Tau regulatory action based on an "alternative core" of microtubule binding and regulatory activities composed of two repeats and the interrepeat between them. In this model, the interrepeat serves as the primary regulator of microtubule dynamics, whereas the flanking repeats serve as tethers to properly position the interrepeat on the microtubule. Importantly, since there are multiple interrepeats on each Tau molecule, there are also multiple cores on each Tau molecule, each with distinct mechanistic capabilities, thereby providing significant regulatory potential. Taken together, the data are consistent with a microtubule misregulation mechanism for Tau-mediated neuronal cell death and provide a novel mechanistic model for normal and pathological Tau action.The microtubule-associated protein Tau is necessary for the establishment of neuronal cell polarity, axonal outgrowth, and axonal transport and the maintenance of axonal morphology (1-5). Tau dysfunction has long been correlated with a variety of neurodegenerative diseases, including Alzheimer disease, fronto-temporal dementia, and Parkinsonism associated with chromosome 17 (FTDP-17), 3 Pick disease, and progressive supranuclear palsy. Each of these diseases is characterized by extensive neuronal cell death and the presence of abnormal pathological fibers composed primarily of hyperphosphorylated Tau (6 -8). In 1998, direct genetic linkages between mutations in the Tau gene and FTDP-17 were reported (9 -12). These mutations all exhibit dominant phenotypes and fall into two classes: structural mutations that alter the encoded sequence of the Tau protein and regulatory mutations that alter the pattern of Tau RNA alternative splicing (13). Mutations in the latter class do not affect the primary sequence of Tau but rather alter the expression ratios of the different wild type isoforms. The fact that such alterations cause neurodegeneration indicates that different Tau isoforms must exert at least some functionally distinct effects.Alternative splicing of Tau RNA produces six different Tau isoforms in the c...

show abstract

Missense tau mutations identified in FTDP-17 have a small effect on tau–microtubule interactions

Cited by 78 publications

References 35 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

Differential regulation of microtubule dynamics by three- and four-repeat tau: Implications for the onset of neurodegenerative disease

FTDP-17 Mutations in Tau Alter the Regulation of Microtubule Dynamics

Contact Info

Product

Resources

About