Modulation of UCH-L1 expression as a therapeutical proposal for neurodegenerative diseases

• Grant number: 23/14960-8
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: June 01, 2024
• End date: May 31, 2028
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Ângela Saito
• Grantee: Estefanny Guimarães de Abreu
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil

Abstract

Neurodegenerative diseases affect millions of people worldwide and there are still no therapies able to reduce the progression of the disease and causing few adverse effects. UCH-L1 is a deubiquitinase enzyme fundamental for ubiquitin level maintenance, regulation of specific protein degradation, and cellular redox state. It is highly expressed in neurons, and in neurodegenerative diseases its expression has been found to be reduced. Knock-out murine models for this enzyme or with loss-of-function mutations present phenotypes similar to those diseases, such as motor deficits and oxidative stress, however, ectopic expression of UCH-L1 in models restored neuronal health and cytoarchitectural integrity. Therefore, a possible therapeutic approach for these diseases is to promote the increase of expression of endogenous UCH-L1 in neurons. The Uchl1 gene promoter contains a repressor site of its expression in neuronal cells responsive to a transcription factor important for neuroinflammation, a condition that is simultaneous and associated with neurodegenerative diseases. Thus, this project aims to develop a gene editing therapy based on the modulation of UCH-L1 expression, using the repressor site of Uchl1 gene as a target, to support the treatment of neurodegenerative diseases. Specifically, this work will carry out mutagenesis of the promoter associated with luciferase reporter assays, standardization of gene editing strategy in neuronal cells, and validation of strategy using in vitro and in vivo models of Alzheimer's disease and Parkinson's disease, evaluating aspects of gene editing efficacy and specificity, as well as disease-related phenotypes before and after application of the therapy. In conclusion, this study may pave the way for a new therapeutic approach for neurodegenerative diseases through modulation of UCH-L1 expression. (AU)