RNA stimulates aggregation of microtubule‐associated protein tau into Alzheimer‐like paired helical filaments

  title={RNA stimulates aggregation of microtubule‐associated protein tau into Alzheimer‐like paired helical filaments},
  author={T Kampers and Peter Friedhoff and Jacek Biernat and Eckhard Mandelkow and Eckhard Mandelkow},
  journal={FEBS Letters},

Purification of recombinant tau protein and preparation of Alzheimer-paired helical filaments in vitro.

This chapter describes the methods necessary for studying the characteristics of tau polymerization to PHFs and describes a purification protocol for recombinantly expressed tau and a general method for the polyanion induced polymerization of t Tau toPHFs.

A nucleated assembly mechanism of Alzheimer paired helical filaments.

It is shown that PHFs arise from a nucleated assembly mechanism that comprises about 8-14 tau monomers, and dimerization and nucleation are the rate-limiting steps for PHF formation in vivo.

Structural Principles of Tau and the Paired Helical Filaments of Alzheimer’s Disease

In the paired helical filaments of Alzheimer’s disease, small segments of tau adopt a β‐conformation and interact with other tau molecules, which gives rise to the fuzzy coat of the filaments.

Conformational transition state is responsible for assembly of microtubule-binding domain of tau protein.

Shapeshifting tau: from intrinsically disordered to paired-helical filaments.

The recently highlighted involvement of low-complexity domains in liquid-liquid phase separation provides a critical link between the soluble function and the insoluble dysfunctional properties of tau.

Aggregation analysis of the microtubule binding domain in tau protein by spectroscopic methods.

The aggregation of 4RMBD was suggested to be a nucleation-dependent process, where the non-covalent dimer acts as an effective structural unit, but the aggregation rate was strongly affected by the point mutation.

Conformation of Human Microtubule Associated Protein-Tau

The results highlight the low hydrophobic content of tau being the main cause for its unfolded nature and the denaturation of PHFs at mild concentrations of GdnHCl as well as the partial dissolution ofPHFs at extreme pHs points to ionic nature of interactions within PHFs.

Assembly of two distinct dimers and higher‐order oligomers from full‐length tau

It is demonstrated that tau assembly involves two distinct dimers that differ in resistance to reduction and that this event is accompanied by cysteine‐independent intermolecular bridging of microtubule‐binding domain, leading to assembly of higher‐order oligomers.

Conformations of microtubule-associated protein Tau mapped by fluorescence resonance energy transfer.

FRET is applied to examine the conformations of soluble Tau using a series of Tau mutants, each carrying one tryptophan and one cysteine (labeled by IEADANS), and the distance between these FRET pairs placed in different domains of Tau is measured.



Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments.

The in vitro assembly of recombinant tau protein and constructs derived from it into PHFs and the synthetic PHFs bound the dye thioflavin S used in Alzheimer disease diagnostics imply that the redox potential in the neuron is crucial for PHF assembly, independently or in addition to pathological phosphorylation reactions.

Alzheimer-like paired helical filaments and antiparallel dimers formed from microtubule-associated protein tau in vitro

EM is used to study several constructs derived from human brain tau and expressed in Escherichia coli to study their self-assembly, finding that constructs corresponding roughly to the repeat region of tau can form synthetic paired helical filaments resembling those from Alzheimer brain tissue.

Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans

It is shown that non-phosphorylated recombinant tau iso-forms with three microtubule-binding repeats form paired helical-like filaments under physiological conditions in vitro, when incubated with sulphated glycosaminoglycans such as heparin or heparan sulphate.

Polymerization of τ into Filaments in the Presence of Heparin: The Minimal Sequence Required for τ ‐ τ Interaction

The ability of τ for self‐assembly could be localized in a short sequence of amino acids present in the tubulin‐binding repeats of the τ molecule.

Domains of tau protein and interactions with microtubules.

The role of the neuronal microtubule-associated protein tau has been studied by generating a series of tau constructs differing in one or several of its subdomains: length and composition of the

Polymerization of Microtubule-associated Protein Tau under Near-physiological Conditions (*)

Tau purified directly from whole brain tissue rather than from microtubules does not polymerize under conditions described in this report, and filaments formed are similar to that of straight filaments seen in Alzheimer's disease neurofibrillary tangles.

Identification of 3‐ and 4‐repeat tau isoforms within the PHF in Alzheimer's disease.

The alignment of cleavage sites at homologous positions within tandem repeats after protease treatment indicates that the tau‐core association is precisely constrained by the tandem repeat structure of the t Tau molecule.

Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease.

  • C. WischikM. Novák A. Klug
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 1988
A substantially enriched preparation of Alzheimer paired helical filaments has been used as a starting point for biochemical studies and sequence analysis of these peptides was used to design oligonucleotide probes for cloning a cognate cDNA, which leads to its identification as human microtubule-associated tau protein.