Role of aldehyde dehydrogenase 2 in Amyotrophic Lateral Sclerosis

• Grant number: 21/10692-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): December 01, 2021
• Effective date (End): November 30, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Marisa Helena Gennari de Medeiros
• Grantee: Bárbara Nunes Krum
• 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 pathophysiology of Amyotrophic Lateral Sclerosis (ALS) has recently established that the formation and accumulation of aldehydes resulting from mitochondrial dysfunction, and consequent excessive lipid peroxidation, are extremely neurotoxic and associated with the appearance of symptoms and progression of ALS in preclinical models. Among different enzymes responsible for cellular detoxification, the aldehyde dehydrogenase 2 (ALDH2), located in the mitochondrial matrix, plays a critical role in eliminating reactive aldehydes. Considering the critical role of aldehydes in the progression of ALS, and the lack of effective therapies in the treatment of the disease, we hypothesize that selective activation of the ALDH2 enzyme, and consequent removal of cytotoxic aldehydes, will lead to an improvement in the mitochondrial bioenergetic profile and redox balance of neurons present in the motor cortex and spinal cord; therefore, resulting in the prevention or delay of the progression of ALS. In that sense, to better understand the role of aldehyde metabolism by ALDH2 in ALS, we propose the following aims: 1. Evaluate the expression and activation profile of ALDH2, as well as the accumulation of aldehyde-proteina ducts in the progression of ALS in male Sprague Dawley rats overexpressing human SOD1-G93A enzyme; 2. test the contribution of pharmacological activation (Alda-1) and inhibition (CVT-10216) of ALDH2 in the progression of ALS in rats. This study is of great value since a more detailed understanding of the role of ALDH2 in ALS may contribute to the future use of therapies that act on key mechanisms involved in the pathophysiology of ALS, such as the ALDH2 activator(Alda-1). (AU)