Biology subjects

Bisi, N.

Publications and source records attributed to Bisi, N..

3 recordsLinked to original sources

bioRxiv2024

Application of modular isoxazoline-β2,2-amino acid-based peptidomimetic foldamers as a chemical model system for studying the tau misfolding mechanism.

Tauopathies are a group of neurodegenerative diseases characterized by the deposition of abnormal aggregates of tau protein into the brain. Tau is a microtubule-associated protein whose physiological role is related to the modulation of microtubule dynamics and the correct axonal transport in neurons. In tauopathies, the mechanism of conversion of the tau molecule from a physiological to a pathological form is still unclear. Nevertheless, two hexapeptide sequences, named PHF6 and PHF6*, located in the R3 and R2 repetition domains of tau, respectively, seem to be crucial in triggering the aggregation. In the native state, the hydrophobic residues of PHF6 and PHF6* are protected by a {beta}-hairpin-like structure. Contrary to that, the misfolded protein exposes hydrophobic residues, which can form hydrophobic interactions and drive the self-assembly process. Chemical model systems, other than being more straightforward and easily accessible than full-length proteins, can provide valuable insight, which is difficult to tease out by studying the natural systems directly, and can especially be employed to examine the structures and modes of folding of amyloid proteins. Here, we exploit the use of chemical systems to modulate and study the mechanism of tau misfolding and aggregation. By employing a new non-natural {beta}2,2-amino acid, we have induced the two hot spot sequences of tau (PHF6 and PHF6*) either to have a totally extended conformation or a {beta}-hairpin, according to the (S) or (R) stereochemistry of the scaffold, respectively. The aim of this work was to provide, through the interchange between {beta}-hairpin-like and extended conformations, a possible explanation for the mechanism of tau misfolding. We demonstrated that an extended conformation, exposing the hydrophobic residues of both sequences and driving away PHF6* from PHF6, can trigger the aggregation of tau and behaves as a seed-competent monomer model system. Conversely, a {beta}-hairpin imitates the favorable folding of tau, allowing the protein to maintain its soluble monomeric form. Furthermore, a {beta}-hairpin mimic, based on the chaperone protein Hsp90, demonstrated the further application of this type of peptidomimetic foldamers as both aggregation inhibitors and chaperone mimics for the corrective folding of tau in a neuronal environment.

biochemistry↗

bioRxiv2024

Synthetic chaperone based on Hsp90-Tau interaction inhibits pathological Tau aggregation and rescues physiological Tau-Microtubule interaction

The accumulation of intracellular aggregates of Tau protein is one main hallmark of Alzheimers disease (AD) and is the consequence of Tau conformational changes, increased phosphorylation, and self-association to form fibrillar aggregates. This pathological process prevents the physiological interaction of Tau with microtubules to the detriment of the structural integrity of neurons. In healthy cells, aberrant protein misfolding and aggregation are counteracted by chaperone proteins whose protective capacity decreases with age. The role of the chaperone Hsp90 and the mechanism by which it can prevent Tau aggregation toxicity are controversial. The innovative strategy of mimicking Hsp90 through the design of the {beta}-hairpin like peptidomimetic {beta}-Hsp90, inspired by two Hsp90/Tau interaction sequences, is presented here. {beta}-Hsp90 inhibits Tau aggregation both in vitro and in cells, restoring Taus physiological interaction with microtubules. {beta}-Hsp90, which interacts with the P1 region of Tau, is more effective than individual peptide sequences from the chaperone HSP90 and another {beta}-hairpin mimic based on Tau sequences. Moreover, {beta}-Hsp90 dramatically reduces AD-associated A{beta}1-42 aggregation, offering the development of a dual inhibitor. This work paves the way for the design of new drugs targeting devastating untreated amyloid diseases, by mimicking physiological chaperones with small synthetic peptide drugs.

pharmacology and toxicology↗

bioRxiv2022

Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule regulation

Tauopathies such as Alzheimers disease are characterized by the aggregation and increased phosphorylation of the microtubule-associated protein tau. The pathological changes in tau are closely linked to neurodegeneration, making tau a prime candidate for intervention. However, the multiple facets of tau function and the lack of cellular tauopathy models that could support mechanism-based drug development hampers progress. Here we report the development of a live-cell imaging approach to quantitatively monitor pathological changes of human tau as it interacts with axonal microtubules. We show that a full-length aggregation-prone tau construct exhibits reduced interaction with microtubules as it increasingly aggregates. Through chemoinformatic analyses, we identified 2-phenyloxazole (PHOX) derivatives as putative polypharmacological small molecules that inhibit tau aggregation and modulate tau phosphorylation. We found that PHOX15 restores the physiological microtubule interaction of aggregation-prone tau in neurons and inhibits the first phase of tau aggregation in vitro. Furthermore, we report that PHOX15 inhibits the tau kinases GSK3{beta} and Cdk5, alters the kinome activity of model neurons, and reduces tau phosphorylation at disease-relevant sites. Molecular dynamics simulations highlight cryptic channel-like pockets crossing tau protofilaments and indicate that the binding of PHOX15 in one of the channels reduces the protofilaments ability to adopt a PHF-like conformation. The data show that our imaging approach provides a useful tool for identifying compounds that modulate tau-microtubule interaction in axons. We demonstrate that a polypharmacological approach to simultaneously treat tau aggregation and tau phosphorylation is able to restore physiological microtubule regulation, identifying PHOX15 as a promising drug candidate to counteract tau-induced neurodegeneration.

neuroscience↗