Microtubule stabilising peptides rescue tau phenotypes in-vivo.

Shmma Quraishe,Amritpal Mudher,Louise Cranfield,Megan Sealey

doi:10.1038/srep38224

Abstract

The microtubule cytoskeleton is a highly dynamic, filamentous network underpinning cellular structure and function. In Alzheimer’s disease, the microtubule cytoskeleton is compromised, leading to neuronal dysfunction and eventually cell death. There are currently no disease-modifying therapies to slow down or halt disease progression. However, microtubule stabilisation is a promising therapeutic strategy that is being explored. We previously investigated the disease-modifying potential of a microtubule-stabilising peptide NAP (NAPVSIPQ) in a well-established Drosophila model of tauopathy characterised by microtubule breakdown and axonal transport deficits. NAP prevented as well as reversed these phenotypes even after they had become established. In this study, we investigate the neuroprotective capabilities of an analogous peptide SAL (SALLRSIPA). We found that SAL mimicked NAP’s protective effects, by preventing axonal transport disruption and improving behavioural deficits, suggesting both NAP and SAL may act via a common mechanism. Both peptides contain a putative ‘SIP’ (Ser-Ile-Pro) domain that is important for interactions with microtubule end-binding proteins. Our data suggests this domain may be central to the microtubule stabilising function of both peptides and the mechanism by which they rescue phenotypes in this model of tauopathy. Our observations support microtubule stabilisation as a promising disease-modifying therapeutic strategy for tauopathies like Alzheimer’s disease.

Highlights

The microtubule cytoskeleton is a highly dynamic, filamentous network underpinning cellular structure and function
Treatment with NAP (NAPVSIPQ known as ‘davunetide’), a small octapeptide derived from activity dependent neuroprotective protein (ADNP)[15] effectively restores MT integrity[14,16] and protects MT-dependent axonal transport in both rodent[17] and Drosophila[14] models of disease
The majority of +TIPs do not interact directly with the MT plus-end and/or MT lattice. This interaction occurs through end-binding proteins (EBs), which recognise and bind conserved Ser-x-Ile-Pro (SxIP) polypeptide motifs within +TIPs21

Summary

Introduction

The microtubule cytoskeleton is a highly dynamic, filamentous network underpinning cellular structure and function. We found that SAL mimicked NAP’s protective effects, by preventing axonal transport disruption and improving behavioural deficits, suggesting both NAP and SAL may act via a common mechanism Both peptides contain a putative ‘SIP’ (Ser-Ile-Pro) domain that is important for interactions with microtubule end-binding proteins. Htau0N3R-expression in this model causes neuronal dysfunction, characterised by MT destabilisation[6], axonal transport disruption[11], synaptic defects[12] and behavioural impairments[11] This model has been used to explore the effectiveness of disease‐ modifying interventions to either reduce tau phosphorylation or enhance MT stabilisation[6,14].

Methods

Results

Conclusion