Functional Genomics of Human Variants Potentially Associated with Amyotrophic Lateral Sclerosis in Brazil

• Grant number: 25/23837-0
• Support Opportunities: Scholarships in Brazil - Program to Stimulate Scientific Vocations
• Start date: January 12, 2026
• End date: March 03, 2026
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Principal Investigator: Rosalia Mendez-Otero
• Grantee: Débora Micalli
• Host Institution: Instituto de Biofísica Carlos Chagas Filho (IBCCF). Universidade Federal do Rio de Janeiro (UFRJ)

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, and fatal neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons, resulting in muscle weakness, atrophy, and respiratory failure, involving oxidative stress, mitochondrial dysfunction, protein aggregation, and impairment of nucleocytoplasmic transport. The genetics of ALS are complex, with more than 40 genes and hundreds of variants potentially involved. Variants in the VAPB and TARDBP genes (which encodes the TDP-43 protein) are among the main known genetic causes of the disease, including in Brazil. The identification and functional characterization of human variants found in patients with ALS, although challenging, can contribute to the understanding of the molecular mechanisms underlying the disease and to the search for new therapeutic targets. Due to the genetic complexity involved in ALS and the rapid progression of the disease, Drosophila melanogaster presents itself as an ideal in vivo system for modeling phenotypes found in ALS, as its genome contains 75% of the genes associated with human pathologies, being highly efficient for the study of human diseases, such as neurodegenerative ones, due to its remarkable genetic conservation, multiple available genetic manipulation tools, and short life cycle. The objective of this project is for the fellow to receive practical training in the production and characterization of transgenic lines of D. melanogaster expressing genes containing variants in TARDBP and VAPB potentially associated with ALS in the Brazilian population. The transgenesis will use the PhiC31 site-specific integration system, and the brains and ventral nerve cords of third-instar larvae and adults will be analyzed by confocal microscopy, with the aim of identifying morphological alterations related to the expression of the human variants. This project will contribute to the understanding of the cellular mechanisms involved in ALS and will strengthen the integration between functional genetics and translational neuroscience. Therefore, the fellow will assist in the development of patient-specific genetic models with an approach that can be expanded beyond ALS, with research perspectives in neurodegenerative diseases in the Brazilian context. (AU)