Effect of Trehalose and Ceftriaxone on the Stability of Aggregating-Prone Tau Peptide Containing PHF6* Sequence: An SRCD Study.

Claudia Honisch,Federica Torni,Paolo Ruzza,Giuliano Siligardi,Rohanah Hussain

doi:10.3390/ijms23062932

Abstract

The tau protein, a soluble protein associated with microtubules, which is involved in the assembly and stabilization of cytoskeletal elements, was found to form neurofibrillary tangles in different neurodegenerative diseases. Insoluble tau aggregates were observed to be organized in paired helical filaments (PHFs) and straight filaments (SFs). Recently, two small sequences (306–311 and 275–280) in the microtubule-binding region (MTBR), named PHF6 and PHF6*, respectively, were found to be essential for tau aggregation. Since a possible therapeutic approach consists of impairing amyloid formation either by stabilizing the native proteins or reducing the level of amyloid precursors, here we use synchrotron radiation circular dichroism (SRCD) at Diamond B23 beamline to evaluate the inhibitory effects of two small molecules, trehalose and ceftriaxone, against the aggregation of a small peptide containing the PHF6* sequence. Our results indicate that both these molecules, ceftriaxone and trehalose, increased the stability of the peptide toward aggregation, in particular that induced by heparin. With trehalose being present in many fruits, vegetables, algae and processed foods, these results support the need to investigate whether a diet richer in trehalose might exert a protective effect toward pathologies linked to protein misfolding.

Highlights

Published: 8 March 2022Intrinsically disordered proteins (IDPs) are a widespread class of proteins with the ability to quickly change their conformations upon participating in biological processes [1].IDP structures are highly controlled in the cell, and aberrant regulation is often associated with protein aggregation and human diseases [2].The tau protein, a soluble protein associated with microtubules whose function is to assist the assembly and stabilization of microtubules and other cytoskeletal elements, represents an archetypical IDP found in the nervous system [3].Neurofibrillary tangles of tau protein occur in neurons and glial cells of patients affected by different neurodegenerative diseases known as tauopathies, including, but not limited to, Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, some frontotemporal dementias and chronic traumatic encephalopathy [4]
Circular dichroism spectroscopy was utilized to monitor the conformational conversion of a short peptide, corresponding to the sequence 273–284 of tau protein and containing the PHF6* region involved in the protein aggregation, induced by lowmolecular-weight heparin
We reported experimental evidence that both these molecules, ceftriaxone and trehalose, interacted with tau peptide in the presence of heparin, increasing the Tm, which is an indication of ligand binding interaction and the increased stability of the peptide toward aggregation, and more importantly, interfering with the peptide aggregation induced by heparin

Summary

Introduction

Published: 8 March 2022Intrinsically disordered proteins (IDPs) are a widespread class of proteins with the ability to quickly change their conformations upon participating in biological processes [1].IDP structures are highly controlled in the cell, and aberrant regulation is often associated with protein aggregation and human diseases [2].The tau protein, a soluble protein associated with microtubules whose function is to assist the assembly and stabilization of microtubules and other cytoskeletal elements, represents an archetypical IDP found in the nervous system [3].Neurofibrillary tangles of tau protein occur in neurons and glial cells of patients affected by different neurodegenerative diseases known as tauopathies, including, but not limited to, Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, some frontotemporal dementias and chronic traumatic encephalopathy [4]. IDP structures are highly controlled in the cell, and aberrant regulation is often associated with protein aggregation and human diseases [2]. The tau protein, a soluble protein associated with microtubules whose function is to assist the assembly and stabilization of microtubules and other cytoskeletal elements, represents an archetypical IDP found in the nervous system [3]. Neurofibrillary tangles of tau protein occur in neurons and glial cells of patients affected by different neurodegenerative diseases known as tauopathies, including, but not limited to, Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, some frontotemporal dementias and chronic traumatic encephalopathy [4]. A strict correlation has been found between the extent and anatomical localization of tau aggregates and the progression of Alzheimer’s disease [5]. Tau aggregates are assembled in insoluble paired helical filaments (PHFs) and straight filaments (SFs) [6]

Methods

Results

Conclusion