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Role of aldehyde dehydrogenase 2 in Amyotrophic Lateral Sclerosis

Grant number: 21/10692-3
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): December 01, 2021
Effective date (End): November 30, 2022
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal researcher:Marisa Helena Gennari de Medeiros
Grantee:Bárbara Nunes Krum
Home 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 theformation and accumulation of aldehydes resulting from mitochondrial dysfunction, andconsequent excessive lipid peroxidation, are extremely neurotoxic and associated with theappearance of symptoms and progression of ALS in preclinical models. Among different enzymesresponsible for cellular detoxification, the aldehyde dehydrogenase 2 (ALDH2), located in themitochondrial matrix, plays a critical role in eliminating reactive aldehydes. Considering the criticalrole of aldehydes in the progression of ALS, and the lack of effective therapies in the treatment ofthe disease, we hypothesize that selective activation of the ALDH2 enzyme, and consequentremoval of cytotoxic aldehydes, will lead to an improvement in the mitochondrial bioenergeticprofile 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 understandthe role of aldehyde metabolism by ALDH2 in ALS, we propose the following aims: 1. Evaluatethe expression and activation profile of ALDH2, as well as the accumulation of aldehyde-proteinadducts 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 moredetailed understanding of the role of ALDH2 in ALS may contribute to the future use of therapiesthat act on key mechanisms involved in the pathophysiology of ALS, such as the ALDH2 activator(Alda-1). (AU)

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