The effect of chronic ethanol consumption in the progression of Amiotrophic Lateral Sclerosis

• Grant number: 24/01049-8
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2024
• End date: April 30, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Julio Cesar Batista Ferreira
• Grantee: Luana Pilone da Silva
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

It is currently known that the pathophysiology of amyotrophic lateral sclerosis (ALS) is associated with mitochondrial dysfunction, excessive lipid peroxidation and consequent accumulation of cytotoxic aldehydes. Among these aldehydes, acetaldehyde can be highlighted, an electrophilic aldehyde produced in the mitochondria capable of attacking nucleophilic amino acids and forming adducts with proteins inactivating them, generating protein aggregates and culminating in cellular dysfunction. One of the enzymes responsible for the elimination of this class of aldehydes is aldehyde dehydrogenase 2 (ALDH2), located in the mitochondrial matrix. At the same time, the consumption of ethanol and its consequent metabolism results in the production and accumulation of acetaldehyde in our body. Upon ingestion, alcohol dehydrogenase (ADH) enzymes transform ethanol into acetaldehyde, and subsequently ALDH2 eliminates these aldehydes, oxidizing them to acetate. The accumulation of acetaldehyde due to chronic ethanol consumption causes neuronal mitochondrial dysfunction and is associated with the onset of neurodegenerative diseases such as Alzheimer's disease. However, its role in the pathophysiology of ALS and motor neuron degeneration has not yet been reported. Thus, the objective of this research proposal is to better understand the possible influence of chronic ethanol intake on the onset and development of ALS.For this, wild and transgenic mice carrying the SOD1*G93A mutation (which causes ALS) will receive daily ethanol (2g/kg/day) or water by gavage over 100 days, starting in the asymptomatic phase of the disease (40 days of life) and ending in the advanced symptomatic phase of ALS (140 days of life). We will evaluate a number of functional and biochemical parameters in different tissues (including motor cortex, spinal cord, skeletal muscle, and plasma) of the animals. To evaluate the locomotor functional parameters, we will perform the open field, rotarod, ambulation, Y-labyrinth, wire hang and grip strength tests in the animals. Among the biochemical parameters, we will analyze the protein expression and catalytic activity of the ALDH2 enzyme, formation of 4-HNE-protein adducts and mitochondrial bioenergetic metabolism (including O2 consumption and H2O2 release) in the motor cortex, spinal cord and skeletal muscles (plantar and soleus muscles). This study is of great value since a more detailed understanding of the role of chronic ethanol consumption in the development of ALS may contribute to an elucidation of the neurodegenerative mechanisms triggered by such consumption.