TY  - JOUR
AU  - Voigt, Aaron
AU  - Herholz, David
AU  - Fiesel, Fabienne C
AU  - Kaur, Kavita
AU  - Müller, Daniel
AU  - Karsten, Peter
AU  - Weber, Stephanie S
AU  - Kahle, Phillip
AU  - Marquardt, Till
AU  - Schulz, Jörg B
TI  - TDP-43-mediated neuron loss in vivo requires RNA-binding activity.
JO  - PLOS ONE
VL  - 5
IS  - 8
SN  - 1932-6203
CY  - San Francisco, California, US
PB  - PLOS
M1  - DZNE-2020-02414
SP  - e12247
PY  - 2010
AB  - 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.
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Animals
KW  - Cell Line
KW  - Chickens: genetics
KW  - Chickens: metabolism
KW  - Chickens: physiology
KW  - DNA-Binding Proteins: genetics
KW  - DNA-Binding Proteins: metabolism
KW  - Drosophila melanogaster: cytology
KW  - Drosophila melanogaster: genetics
KW  - Drosophila melanogaster: metabolism
KW  - Drosophila melanogaster: physiology
KW  - Frontotemporal Lobar Degeneration: genetics
KW  - Gene Expression Regulation
KW  - Humans
KW  - Intracellular Space: metabolism
KW  - Locomotion
KW  - Longevity
KW  - Male
KW  - Motor Neurons: metabolism
KW  - Mutation
KW  - Neurons: cytology
KW  - Neurons: metabolism
KW  - Organ Specificity
KW  - Protein Binding
KW  - Protein Transport
KW  - RNA: metabolism
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - RNA (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:20806063
C2  - pmc:PMC2923622
DO  - DOI:10.1371/journal.pone.0012247
UR  - https://pub.dzne.de/record/136092
ER  -