Structure, Stability, and Aggregation of Paired Helical Filaments from Tau Protein and FTDP-17 Mutants Probed by Tryptophan Scanning Mutagenesis

Li, Li; Bergen, Martin von; Mandelkow, Eva‐Maria; Mandelkow, Eckhard

doi:10.1074/jbc.m206334200

Cited by 69 publications

(68 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tau oligomerization could play a key role in either mechanism. For example, several authors have suggested that the FTDP-17 tau mutations causing amino acid substitutions lead to an increased probability of forming abnormal tau oligomers and then fibers (paired helical filaments/ neurofibrillary tangles) (46,47). Abnormal oligomerization, the gained function, could be a precursor state to assembly of the larger cytotoxic fibers.…”

Section: Molecular Mechanisms By Which Tauopathies May Results In Neurmentioning

confidence: 99%

Microtubule-dependent Oligomerization of Tau

Makrides

Shen

Bhatia

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

The accumulation of abnormal tau filaments is a pathological hallmark of many neurodegenerative diseases. In 1998, genetic analyses revealed a direct linkage between structural and regulatory mutations in the tau gene and the neurodegenerative disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Importantly, the FTDP-17 phenotype is transmitted in a dominant rather than a recessive manner. However, the underlying molecular mechanisms causing disease remain uncertain. The most common molecular mechanism generating dominant phenotypes is the loss of function of a multimeric complex containing both mutant and wild-type subunits. Therefore, we sought to determine whether tau might normally function as a multimer. We co-incubated 35 S-radiolabeled tau and biotinylated tau with taxol stabilized microtubules, at very low molar ratios of tau to tubulin. Subsequent covalent cross-linking followed by affinity-precipitation of the biotinylated tau revealed the formation of microtubule-dependent tau oligomers. We next used atomic force microscopy to independently assess this conclusion. Our results are consistent with the hypothesis that tau forms oligomers upon binding to microtubules. In addition to providing insights into normal tau action, our findings lead us to propose that one mechanism by which mutations in tau may cause cell death is through the formation of tau complexes containing mutant tau molecules in association with wild-type tau. These wildtype-mutant tau complexes may possess altered biological and/or biophysical properties that promote onset of the FTDP-17 phenotype, including neuronal cell death by either altering normal tau-mediated regulation of microtubule-dependent cellular functions and/or promoting the formation of pathological tau aggregates.The microtubule-associated protein tau, localized predominantly in the cell bodies and axons of neuronal cells, is necessary for the establishment of neuronal cell polarity and axon outgrowth, for axonal transport, and the maintenance of axonal morphology (for example, see Refs. 1-6). Tau is also expressed in glial cells (7), although its role (8) there are less defined.Mechanistically, tau is well known to stimulate MT 1 polymerization, to stabilize MTs, and to modulate MT dynamics (9 -12). Since MT dynamics must be tightly regulated for cells to function and remain viable (e.g. see Refs. 13 and 14), it follows that tau action must also be finely regulated in cells.Alternatively, abnormal tau behavior is often associated with neurodegenerative diseases. In Alzheimer's disease, FTDP-17 and a large number of additional "tauopathies," necrotic neurons possess abnormal pathological fibers composed primarily of hyperphosphorylated and dysfunctional tau (for a recent review, see Ref. 15). Until recently, the relationship between tau and these various diseases was only correlative. However, in 1998, several groups reported a direct genetic linkage between mutations in the tau gene and FTDP-17, a group of related neurodegenerative con...

show abstract

Section: Molecular Mechanisms By Which Tauopathies May Results In Neurmentioning

confidence: 99%

Microtubule-dependent Oligomerization of Tau

Makrides

Shen

Bhatia

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…PHF assembly appears to occur in stages (Friedhoff et al, 1998), and this noncross-linked, phosphorylated tau protein may represent a stage of PHF formation in which tau aggregates are unstable. When anionic inducing agents stimulate PHF formation in vitro, the stability of the tau aggregates and resistance to denaturation is low (Li et al, 2002). However, combining transglutaminase with tau in vitro results in stable, insoluble tau filaments (Dudek and Johnson, 1993;Appelt and Balin, 1997) that are biochemically similar to PHF from AD (Selkoe et al, 1982a).…”

Section: Discussionmentioning

confidence: 99%

Tau Protein Is Cross-Linked by Transglutaminase in P301L Tau Transgenic Mice

Halverson¹,

Lewis²,

Frausto³

et al. 2005

J. Neurosci.

View full text Add to dashboard Cite

The microtubule-associated protein tau is highly soluble under physiological conditions. However, in tauopathies, tau protein aggregates into insoluble filaments and neurofibrillary tangles (NFTs). The mechanisms underlying the formation of tau filaments and NFTs in tauopathies remain unclear. Several lines of evidence suggest that transglutaminase may cross-link tau into stable, insoluble aggregates, leading to the formation of NFTs in Alzheimer's disease and progressive supranuclear palsy. To further determine the contribution of transglutaminase in the formation of NFTs, we compared the levels of cross-linked tau protein from P301L tau transgenic mice that develop NFTs to four-repeat wild-type (4RWT) tau transgenic and nontransgenic mice that do not develop NFT pathology. Immunoprecipitation and immunoblotting experiments show that transglutaminase cross-links phosphorylated tau in the hindbrain of P301L tau transgenic mice but not in mice overexpressing 4RWT tau and nontransgenic mice. Cross-linked, phosphorylated tau from P301L tau transgenic mice runs as high-molecular mass aggregates on Western blots, similar to cross-linked tau from paired helical filaments of Alzheimer's disease. We also used double-label immunofluorescence to demonstrate colocalization of PHF-1-immunoreactive tau and the transglutaminase-catalyzed cross-link in the hindbrain, spinal cord, and cortex of P301L tau transgenic mice. In the spinal cord, 87% of PHF-1-labeled cells colocalize with the transglutaminase-catalyzed cross-link. Additionally, transglutaminase enzymatic activity is significantly elevated in the spinal cord of P301L tau transgenic mice. These studies further implicate transglutaminase in the formation and/or stabilization of NFT and paired helical filaments and provide a model system to investigate the therapeutic potential of transglutaminase inhibitors in tauopathies.

show abstract

“…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). The final important clue to tau action provided by the FTDP-17 mutations is that all of the mutations exhibit dominant rather than recessive phenotypes.…”

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.

245

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

Structure, Stability, and Aggregation of Paired Helical Filaments from Tau Protein and FTDP-17 Mutants Probed by Tryptophan Scanning Mutagenesis

Cited by 69 publications

References 52 publications

Microtubule-dependent Oligomerization of Tau

Microtubule-dependent Oligomerization of Tau

Tau Protein Is Cross-Linked by Transglutaminase in P301L Tau Transgenic Mice

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

Contact Info

Product

Resources

About