TDP-43 Overexpression Enhances Exon-7 Inclusion during SMN Pre-mRNA Splicing
Date Issued
2008
Date
2008
Author(s)
Krishnan, Bose Jayarama
Abstract
TDP-43 is a highly conserved, 43 kDa RNA-binding protein implicated to play a role in transcription repression, nuclear organization, and alternative splicing. More recently, TDP-43 has been identified as the major disease protein of several neurodegenerative diseases including frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). For the splicing activity, TDP-43 has been shown to be mainly an exon-skipping promoter. In this study using the Survival of Motor Neuron (SMN) minigenes as the reporters in transfection assay, I show for the first time that TDP-43 could also act as an exon-inclusion factor. Furthermore, both RRM domains are required for the ability of TDP-43 to enhance the SMN2 exon 7-inclusion. Combined protein-immunoprecipitation (IP) and RNA-IP experiments also suggested that the exon-inclusion by TDP-43 might be mediated by multimeric complex(es) consisting of TDP-43 interacting with other splicing factors including Htra2-β1. My data further evidences TDP-43 as a multifunctionalNA-binding protein for a diverse set of cellular activities.
Subjects
SMN Exon-7
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