Autosomal dominant dementia with widespread neurofibrillary tangles

Reed, Lee A.; Schelper, Robert L.; Solodkin, Ana; Hoesen, Gary W. Van; Morris, John C.; Trojanowski, John Q.; Grabowski, Thomas J.; Talbot, Chris J.; Schmidt, Maria Luiza Gava; Goate, Alison M.; Wragg, Michelle

doi:10.1002/ana.410420406

Cited by 173 publications

(172 citation statements)

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“…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.…”

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confidence: 60%

“…Our group has previously shown that osmotic stress of SH-SY5Y cells results in activation of an apoptotic cascade (46). Because the R406W tau mutation is reported to have a relatively mild phenotype in the families (30) and therefore under normal conditions may not be toxic to cells, the cells were subjected to osmotic stress to determine if R406W mutant tau-expressing CN1.4 cortical cells were more vulnerable compared with cells expressing wild type tau. The results clearly demonstrated that R406W mutant tau does in fact exert a toxic effect under stress conditions in our cortical cell model, because there was more caspase activation in cells expressing R406W mutant tau compared with cells expressing wild type tau.…”

Section: Cellular Localization Of Wild Type and Mutant R406wmentioning

confidence: 99%

“…Therefore the effects of the R406W tau mutation on microtubule binding and function remain to be fully established. In addition, stable or transient transfection of R406W tau into non-neural cell lines has resulted in R406W tau being less phosphorylated than the wild type tau (23,34), even though the tau from R406W FTDP-17 cases is hyperphosphorylated (30,31).…”

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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 R406wmentioning

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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“…The morphologies of tau filaments observed in the various forms of FTDP-17T vary (Crowther and Goedert 2000). Some mutations, such as V337M and R406W, produce filaments that appear identical to the paired helical and straight filaments of Alzheimer disease (Spillantini et al 1996;Reed et al 1997;Hutton et al 1998;Poorkaj et al 1998). All six tau isoforms are affected by the mutations and are incorporated into the filaments, which give rise to a pattern of tau bands on SDS-PAGE identical to that seen in Alzheimer disease.…”

Section: Implications For Understanding Alzheimer Diseasementioning

confidence: 99%

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

Goedert¹,

Ghetti²,

Spillantini³

2011

Cold Spring Harbor Perspectives in Medicine

138

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“…Among them, R406W mutant tau showed significantly reduced phosphorylation in those experiments. However, both mutant tau and wildtype tau deposited in FTDP-17 brains are also hyperphosphorylated (18,19). It is important to resolve the discrepancy between the reduced phosphorylation of mutant tau in vitro and in cultured neurons and the high phosphorylation of mutant tau in pathological brains.…”

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confidence: 99%

Phosphorylation of FTDP-17 Mutant tau by Cyclin-dependent Kinase 5 Complexed with p35, p25, or p39

Sakaue

Saito

Satō

et al. 2005

Journal of Biological Chemistry

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Neurofibrillary tangles are one of the major pathological hallmarks of Alzheimer disease (AD).1 Neurofibrillary tangles are bundles of paired helical filament composed of the microtubule (MT)-associated protein tau in a hyperphosphorylated state (1, 2). Intracellular inclusions made of tau are also found in several other neurodegenerative diseases, including Pick disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17), collectively called tauopathies (3, 4). Exonic and intronic mutations in the tau gene have recently been identified in familial FTDP-17 (5-7), indicating that dysfunction of the tau protein can cause the above mentioned neurodegenerative diseases. Many of the exonic mutations reduce the ability of tau to promote MT assembly (8 -10), but why these mutations cause the formation of tau inclusions is unknown.The tau protein in inclusions is hyperphosphorylated. Around 25 phosphorylation sites have been identified in paired helical filament tau from AD brains (11-13). Characteristic phosphorylation sites are Ser or Thr residues followed by Pro that are phosphorylated by the proline-directed protein kinase activities of extracellular signal-regulated kinase, glycogen synthase kinase 3␤ (GSK3␤), and cyclin-dependent kinase 5 (Cdk5). Phosphorylation reduces the ability of tau to bind to and polymerize MTs, resulting in an increase in the soluble form of tau dissociated from MTs. However, it is unclear how phosphorylated soluble tau assembles into filamentous aggregates of neurofibrillary tangles and then induces neurodegeneration. Elucidating the relationship between tau phosphorylation and aggregate formation is critical to our understanding of the pathogenesis. Phosphorylation of FTDP-17 mutant tau has been studied mainly with GSK3␤ or in non-neuronal cultured cells (14 -17). Mutant tau proteins were not phosphorylated more than wild-type (WT) tau either in transfected cultured cells or in vitro. Among them, R406W mutant tau showed significantly reduced phosphorylation in those experiments. However, both mutant tau and wildtype tau deposited in FTDP-17 brains are also hyperphosphorylated (18,19). It is important to resolve the discrepancy between the reduced phosphorylation of mutant tau in vitro and in cultured neurons and the high phosphorylation of mutant tau in pathological brains.Cdk5 is a proline-directed Ser/Thr kinase activated by a p35 or p39 Cdk5 activator (20 -22). Cdk5 activity is primarily detected in differentiated neurons because p35 and p39 show limited expression in neurons. As described above, Cdk5 is one of the tau protein kinases that phosphorylate tau in living neurons and is also able to generate several paired helical filament epitopes of tau in AD (23,24). However, the phosphorylation of FTDP-17 mutant tau by Cdk5 has not yet been examined. This question should be addressed because the involvement of Cdk5 in the pathogenic phosphorylation of tau has recently become more evident (25,26). In ...

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Autosomal dominant dementia with widespread neurofibrillary tangles

Cited by 173 publications

References 58 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

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

Phosphorylation of FTDP-17 Mutant tau by Cyclin-dependent Kinase 5 Complexed with p35, p25, or p39

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