title: TDP-43-mediated neuron loss in vivo requires RNA-binding activity.
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.
authors.affiliation: Department of Neurology, University Medical Center, RWTH Aachen, Aachen, Germany.
authors.forename: Aaron
authors.initials: A
authors.lastname: Voigt
authors.forename: David
authors.initials: D
authors.lastname: Herholz
authors.forename: Fabienne C
authors.initials: FC
authors.lastname: Fiesel
authors.forename: Kavita
authors.initials: K
authors.lastname: Kaur
authors.forename: Daniel
authors.initials: D
authors.lastname: Müller
authors.forename: Peter
authors.initials: P
authors.lastname: Karsten
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Weber
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Kahle
authors.forename: Till
authors.initials: T
authors.lastname: Marquardt
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000818:Animals; D002460:Cell Line; D002645:Chickens / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008124:Locomotion; D008136:Longevity; D008297:Male; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009928:Organ Specificity; D011485:Protein Binding; D021381:Protein Transport; D012313:RNA / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D012313:RNA
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