Investigation of the potential protective effect of bis-allylic deuterated docosahexaenoic acid as ferroptosis suppressor in amyotrophic lateral sclerosis

• Grant number: 23/12767-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2023
• End date: September 30, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Sayuri Miyamoto
• Grantee: Tiago Eugênio Oliveira da Silva
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/07937-8 - Redoxome - Redox Processes in Biomedicine, AP.CEPID

Abstract

The amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by death of motor neurons in brain and spinal cord, leading to muscular atrophy, paralysis, and death. Importantly, alterations in lipid metabolism due to chronic inflammation and oxidative stress are strongly linked to ALS. The central nervous system (CNS) is enriched in polyunsaturated fatty acids (PUFAs), specially the arachidonic (ARA) and docosahexaenoic (DHA) acids that are highly prone to undergo peroxidation due the presence of several bis-allylic hydrogens. Increasing attention has been given to the role of oxidized lipids or oxylipins in ALS and other neurodegenerative diseases. In this project, experiments using mice and cell lines models for ALS will be combined with mass spectrometry techniques to access oxylipin metabolism and to test the protective effects of bis-allylic deuterium reinforced PUFAs (or D-PUFAs) supplementation. Employed successfully in an array of cellular and animal models, the substitution of bis-allylic H to D has been demonstrated to reduce lipid peroxidation sensitivity. Using a set of D-PUFAs, in vitro experiments are aimed to test to test whether D-PUFA protects cells against death induced by inhibition of GPX4 and lipid droplets. Uniquely designed for this project, synthesis of lysophosphatidylcholine esterified to D-PUFAs will be used to enhance the delivery of these antioxidants across the blood-brain barrier of ALS mice. Our general hypothesis is that a more detailed understanding of PUFA (DHA) metabolism and oxidation, coupled with efficient delivery strategies of PUFAs in the CNS will increase the probability of protection of D-PUFAs against lipid peroxidation in ALS.