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Research on truncated mRNA transcripts susceptible to nonsense-mediated decay in neuronal models

Grant number: 14/25758-6
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): January 01, 2015
Effective date (End): December 31, 2015
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Katlin Brauer Massirer
Grantee:Felipe Eduardo Ciamponi
Home Institution: Centro de Biologia Molecular e Engenharia Genética (CBMEG). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:12/00195-3 - Post-transcriptional regulatory networks mediated by RNA binding proteins in human pluripotent stem cells, AP.JP

Abstract

TDP-43 is one the proteins involved in mRNA splicing, during the processing of pre-mRNAs into mature mRNAs transcripts. When TDP-43 is mutated, this process can be compromised and the newly generated transcripts can show sequence errors. Among the flaws related to the process of splicing, there are mutations called "non-sense", which result in the introduction of a premature stop-codon in the mature mRNA sequence. These codons should be recognized by the cellular quality control system known as Nonsense-Mediated Decay (NMD), a mRNA surveillance pathway. These transcripts should be eliminated by the NMD pathway, preventing the production on truncated proteins, which are non-functional. When this system fails, there is an accumulation of defective transcripts, which can be deleterious to the cell, because defective proteins may form aggregates that can show cellular toxicity. This accumulation of mRNA or protein aggregates in the brain is characteristic for neurodegenerative diseases, such as the Amyotrophic Lateral Sclerosis (ALS). As a hypothesis for this project, we suggest that truncated mRNAs present in the ALS disease can accumulate due to the low activity of the NMD pathway in neuronal cells. This seems to be related to the action of the microRNA mir-128 present in the neuronal tissues. We propose that the induced block of the NMD pathway in cells will result in the stabilization and accumulation of mutated transcripts. In order to asses this mechanism, we will combine public bioinformatics data with gene expression experiments. Experimentally, we are going to asses if the higher presence of truncated mRNAs in mouse brain tissues, compared with other mouse tissues, can explain the lower activity of the NMD pathway and its relation with diseases. (AU)