Voigt, A., Herholz, D., Fiesel, F.C., Kaur, K., Müller, D., Karsten, P., Weber, S.S., Kahle, P.J., Marquardt, T., Schulz, J.B. (2010). TDP-43-Mediated Neuron Loss In Vivo Requires RNA-Binding Activity. PLoS ONE 5(8): e12247.
FlyBase ID
FBrf0211667
Publication Type
Research paper
Abstract
Alteration and/or mutations of the ribonucleoprotein TDP-43 have been firmly linked to human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The relative impacts of TDP-43 alteration, mutation, or inherent protein function on neural integrity, however, remain less clear--a situation confounded by conflicting reports based on transient and/or random-insertion transgenic expression. We therefore performed a stringent comparative investigation of impacts of these TDP-43 modifications on neural integrity in vivo. To achieve this, we systematically screened ALS/FTLD-associated and synthetic TDP-43 isoforms via same-site gene insertion and neural expression in Drosophila; followed by transposon-based motor neuron-specific transgenesis in a chick vertebrate system. Using this bi-systemic approach we uncovered a requirement of inherent TDP-43 RNA-binding function--but not ALS/FTLD-linked mutation, mislocalization, or truncation--for TDP-43-mediated neurotoxicity in vivo.
