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Use and Application of Human Sensorimotor Organoids in Amyotrophic Lateral Sclerosis: Role of the Mitochondrial Enzyme Aldehyde Dehydrogenase 2

Grant number: 23/15607-0
Support Opportunities:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): July 01, 2024
Effective date (End): December 31, 2024
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:Marisa Helena Gennari de Medeiros
Grantee:Bárbara Nunes Krum
Supervisor: Joao Duarte Tavares da Silva Pereira
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: Yale School of Medicine (YSM), United States  
Associated to the scholarship:21/10692-3 - Role of aldehyde dehydrogenase 2 in Amyotrophic Lateral Sclerosis, BP.PD

Abstract

Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder affecting over 250.000 people worldwide. ALS primarily impacts motor neurons, ultimately leading to cell death and a loss of enervation of the neuromuscular junction (NMJ) that precedes the onset of clinical symptoms. More recently, NMJ degeneration has been associated with mitochondrial dysfunction in ALS, but whether mitochondria could be targeted effectively for novel therapeutic intervention in ALS needs to be determined. Aldehyde dehydrogenase 2 (ALDH2) is a major mitochondrial enzyme involved in aldehyde clearance. Our previous findings (from this study) suggest that aldehyde clearance is impaired in SODG93A mutation-induced ALS mice. Moreover, a selective ALDH2 activator (AD6626) improves the clearance of aldehydes generated during mitochondrial dysfunction in ALS mice, which is sufficient to mitigate its progression. Supporting these findings, ALS progression is faster in genetically modified ALDH2 knockin mice carrying the E504K mutation (also present in ~540 million people worldwide), which display defective aldehyde clearance. Here, we propose to characterize the role of ALDH2 and aldehyde metabolism in human sensorimotor organoids derived from healthy and ALS pluripotent stem cells (iPSCs) containing physiologically functional NMJs. This strategy will allow us to expand the understanding of the pathophysiology mechanisms of ALS by studying the effect of aldehyde overload, ALDH2 mutation, and pharmacological ALDH2 activation in human NMJ organoids.

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