TDP-43-mediated neuron loss In Vivo requires RNA-binding activity

Aaron Voigt, David Herholz, Fabienne C. Fiesel, Kavita Kaur, Daniel Müller, Peter Karsten, Stephanie S. Weber, Philipp J. Kahle, Till Marquardt, Jörg B. Schulz

Research output: Contribution to journalArticlepeer-review

135 Scopus citations

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.

Original languageEnglish (US)
Article numbere12247
JournalPloS one
Volume5
Issue number8
DOIs
StatePublished - 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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