Beta Amyloid Peptide:Research Paper: Dual Targeting of Monomeric Tau and α-Synuclein Aggregation: A New Multitarget Therapeutic Strategy for Neurodegeneration

Dual Targeting of Monomeric Tau and α-Synuclein Aggregation: A New Multitarget Therapeutic Strategy for Neurodegeneration

Abstract

Development of efficient multitargeted therapeutic strategies is crucial in facing the multifaceted nature of neurodegenerative diseases. Parkinson's disease (PD) and Alzheimer's disease (AD), the two most common neurodegenerative disorders, share a common hallmark of accumulation of misfolded protein aggregates which are Lewy bodies (LBs) and neurofibrillary tangles (NFTs), respectively. Tau protein and α-synuclein (α-syn), the precursors of LBs and NFTs, have demonstrated synergistic aggregation and neurotoxicity in both in vitro and in vivo models. Herein, we validate for the first time dual targeting of monomeric tau and α-syn aggregation as an efficient platform for development of multitarget therapeutics for neurological disorders. Cellular fluorescence resonance energy transfer (FRET)-based high-throughput screening for tau-binding compounds, followed by additional screening of the hits for their ability to impede α-syn aggregation identified MG-2119 as a potential lead. The high binding affinity of MG-2119 to monomeric tau was verified using cellular FRET assay, isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), and microscale thermophoresis (MSH). Moreover, MG-2119 inhibited α-syn aggregation as revealed by thioflavin T (ThT) assay and dynamic light scattering (DLS) measurements. Interestingly, MG-2119 was capable of rescuing combined tau and α-syn-induced cytotoxicity in SH-SY5Y neuroblastoma cells in a dose-dependent manner. Less pronounced cell-rescuing effects were observed for single-targeted tau and α-syn aggregation inhibitors showcasing the superiority of the multitargeted approach described in this study. The satisfactory pharmacokinetic profile and low toxicity of MG-2119 hold promise for future optimization to develop potential therapeutics for neurological disorders.

Keywords: Tau protein; multitargeted therapeutics; neurodegeneration; α-synuclein.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/32579329/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.