TDP-43-mediated neuron loss in vivo requires RNA-binding activity.
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.
Voigt
Aaron
A
Department of Neurology, University Medical Center, RWTH Aachen, Aachen, Germany.
Herholz
David
D
Fiesel
Fabienne C
FC
Kaur
Kavita
K
Müller
Daniel
D
Karsten
Peter
P
Weber
Stephanie S
SS
Kahle
Philipp J
PJ
Marquardt
Till
T
Schulz
Jörg B
JB
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*
D004268:DNA-Binding Proteins; D012313:RNA
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