Studies on Amyotrophic Lateral Sclerosis type 8 physiopathology through induced pluripotent stem cell models

• Grant number: 21/05194-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2022
• End date: April 30, 2025
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Mayana Zatz
• Grantee: Danyllo Felipe de Oliveira
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Amyotrophic Lateral Sclerosis type 8 (ALS8) is a monogenic, autosomal dominant, type of motor neuron disease. Currently, the commonest pathogenic variant associated with this disorder is a missense mutation in VAPB gene (p.P56S), identified in a large Brazilian genealogy. ALS8 is also notable for its wide variability in clinical manifestations and onset of symptoms, characteristics which have puzzled researchers since its description. Recently, we have studied five ALS8 carrierswith the very same mutation but different rates of clinical progression. Induced Pluripotent Stem Cell (iPSCs) - derived motor neurons were obtained from these individuals, and employed for functional and genome-wide gene expression studies. Through these assays, we were able to identify 66 downregulated and 43 upregulated genes, present in both ALS8 mild individuals, when compared to the three severely affected ones. Owing to the known association of most of the identified genes with the altered molecular processes in these cells (energetic metabolism, cell viability and protein synthesis), we hypothesized they could be genetic modifiers of ALS8 pathogenesis. Based on this, the present work aims to evaluate the process of proteic translation in motor neurons and its relationship with mitochondrial metabolism. We aim, with these experiments, to outline central aspects of Amyotrophic Lateral Sclerosis type 8 physiopathology. This knowledge will be fundamental for devising therapeutic interventions, enabling effective treatments for this neurological condition (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SADOK, SARA H.; BORGES-MEDEIROS, RAYSSA L.; DE OLIVEIRA, DANYLLO F.; ZATZ, MAYANA; DE OLIVEIRA, JOAO DICARDO MENDES. Report of a young patient with brain calcifications with a novel homozygous MYORG variant. Gene, v. 859, p. 3-pg., 2023-01-30. (21/05194-4)

OLIVEIRA, D.; ASSONI, A. F.; ALVES, L. M.; SAKUGAWA, A.; MELO, U. S.; TELES ESILVA, A. L.; SERTIE, A. L.; CAIRES, L. C.; GOULART, E.; GHIROTTO, B.; et al. ALS-associated VRK1 R321C mutation causes proteostatic imbalance and mitochondrial defects in iPSC-derived motor neurons. Neurobiology of Disease, v. 198, p. 8-pg., 2024-05-31. (13/08028-1, 21/05194-4)