Exploring Mechanisms to Combat Alzheimer’s Disease Through Advanced Computational and Synthetic Methods

Alzheimer’s Disease (AD) is one of the most prevalent neurodegenerative diseases in Ireland, posing significant challenges to healthcare systems and affecting countless families. The abnormal misfolding of proteins, particularly Tau, is a hallmark of this disease. The Tau protein plays a vital role in stabilising microtubules, which are essential for their normal neuronal function. However, in AD, Tau undergoes hyper-phosphorylation at serine residues, resulting in dysfunction. 

This research, led by Martina Tuberti, Dr Fintan Kelleher, and Dr Gemma Kinsella from TU Dublin, aims to explore whether the enzymatic beta-elimination of phosphoserines, a mechanism observed in bacteria, could also apply to the Tau protein in human brains. The study focuses on understanding Tau misfolding and discovering potential therapeutic strategies to combat AD, a growing concern in Irish society. 

Phosphorylated Chain pSer356 and Lys357 

In this video, it is a phosphopeptide fragment (Leu352-Lys357) simulation. During the simulations, pSer356 and Lys357 are interacting. This could explain a possible aggregation mechanism. 

Watch the Video 

The project employs a combination of computational analysis and synthetic methods. Initially, the team conducted detailed computational studies to identify a phosphoserine-containing Tau protein pentapeptide fragment. This fragment was subsequently synthesised using Solid Phase Peptide Synthesis (SPPS), which involves building peptides in a stepwise manner on a solid support. The presence of the phosphopeptide fragment was confirmed through Liquid Chromatography-Mass Spectrometry (LC-MS) analysis, which also detected a minor amount of Dha-containing peptide. 

Further computational and synthetic work is planned to investigate the aqueous stability of these peptides under various pH levels. The team uses high-performance computational resources to model these peptide interactions, with the aim of advancing knowledge about Tau misfolding mechanisms. 

HPC Resources:       

This project was allocated 10,000 hours on Kay and most recently 25,000 hours on MeluXina.

The outcomes of this research could revolutionise our understanding of Tau misfolding in Alzheimer’s Disease. By identifying specific mechanisms, such as phosphoserine beta-elimination, that contribute to Tau dysfunction, the team aims to open new therapeutic avenues. This could pave the way for novel treatments targeting the misfolding and aggregation of Tau protein. Such developments offer hope for more effective intervention strategies for Alzheimer’s disease patients. The research not only contributes to the scientific community but also has the potential to reduce the societal burden of Alzheimer’s disease in Ireland and beyond. 

Fintan Kelleher is the leader of the Molecular Design & Synthesis Group, with over 30 years of experience in research in both Industrial and Academic settings. From 1991-1997 he was a Senior Research Chemist in the Medicinal Chemistry Department of the Neuroscience Research Centre of MSD, UK. There he worked on projects related to diseases of the CNS and was part of the team which developed Emend®, for Chemotherapy-Induced Nausea and Vomiting, which was approved for use by the FDA and EMA in 2004. He is the Founder of AMR Ireland (www.amr.ie), a network to help to address the global public health crisis that is Antimicrobial Resistance.  

In TU Dublin, he has supervised 19 PhD and MSc research students to completion. He is a Fellow of the Royal Society of Chemistry and the Institute of Chemistry in Ireland, as well as being a Chartered Chemist and Chartered Scientist. His research funders include SFI, IRC, EPA, EI, HEA (PRTLI), and TU Dublin. He has collaborative links with researchers in Ireland (UCC, RCSI, DCU, ICHEC, Maynooth University, and TCD) and Internationally (Germany, France, Netherlands, and the UK), as well as industry links with MNCs, including Ipsen, Henkel, and Glanbia. 

Dr Gemma Kinsella received a first-class honors B.A. Mod in ‘Computational Chemistry’ as well as her PhD from the Department of Chemistry in Trinity College Dublin (TCD) and subsequently was a postdoctoral fellow in the Molecular Design Group (MDG) in the Department of Biochemistry, TCD. She worked with the Irish Centre for High End Computing (ICHEC) and IBM before completing an IRCSET and a HRB postdoctoral fellowship in the Membrane Protein Lab, of the Department of Biology, NUIM.  

She completed a Postgraduate Diploma in Higher Education, in Maynooth University in 2014. She has lectured in the School of Food Science and Environmental Health in TU Dublin since 2015 and became Head of Food Science and Industrial Biotechnology in 2022. 

Martina Tuberti is currently a PhD student in Chemistry at Technological University of Dublin under the supervision of Dr. Kelleher and Dr. K. Kinsella. She received her master's degree in Italy doing a thesis in collaboration with the University of Granada (Spain) with a project focused on Computational and Medicinal Chemistry.  

After that, she was a visiting postgraduate at the University of Nottingham (UK), improving her computational techniques. Although the current project involves synthetic and computational approaches, she has gradually acquired interest not only in Molecular Modeling but also Quantum Mechanics. She presented her PhD job in more than 10 conferences.