Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0180828
Title: Drosophila lines with mutant and wild type human TDP-43 replacing the endogenous gene reveals phosphorylation and ubiquitination in mutant lines in the absence of viability or lifespan defects
Authors: Chang J.-C. 
Morton D.B.
Keywords: mutant protein
proteasome
TAR DNA binding protein
DNA binding protein
TDP-43 protein, human
adult
age
aged
animal experiment
animal tissue
Article
behavior disorder
controlled study
cytoplasm
developmental disorder
Drosophila
embryo
female
gene mutation
genetic transcription
genome
heredity
hTDP 43 gene
immunoprecipitation
longevity
male
nerve cell
nonhuman
protein function
protein localization
protein phosphorylation
ubiquitination
wild type
aging
animal
cytology
Drosophila melanogaster
genetics
growth, development and aging
human
longevity
metabolism
mutation
phosphorylation
physiology
protein processing
signal transduction
taxis response
transgene
transgenic animal
ubiquitination
Aging
Animals
Animals, Genetically Modified
DNA-Binding Proteins
Drosophila melanogaster
Female
Humans
Longevity
Male
Mutation
Neurons
Phosphorylation
Protein Processing, Post-Translational
Signal Transduction
Taxis Response
Transgenes
Ubiquitination
Issue Date: 2017
Citation: Chang J.-C., Morton D.B. (2017). Drosophila lines with mutant and wild type human TDP-43 replacing the endogenous gene reveals phosphorylation and ubiquitination in mutant lines in the absence of viability or lifespan defects. PLoS ONE 12 (7) : e0180828. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0180828
Abstract: Mutations in TDP-43 are associated with proteinaceous inclusions in neurons and are believed to be causative in neurodegenerative diseases such as frontotemporal dementia or amyotrophic lateral sclerosis. Here we describe a Drosophila system where we have engineered the genome to replace the endogenous TDP-43 orthologue with wild type or mutant human TDP-43(hTDP-43). In contrast to other models, these flies express both mutant and wild type hTDP-43 at similar levels to those of the endogenous gene and importantly, no age-related TDP-43 accumulation observed among all the transgenic fly lines. Immunopre-cipitation of TDP-43 showed that flies with hTDP-43 mutations had increased levels of ubiquitination and phosphorylation of the hTDP-43 protein. Furthermore, histologically, flies expressing hTDP-43 M337V showed global, robust neuronal staining for phospho-TDP. All three lines: wild type hTDP-43, -G294A and -M337V were homozygous viable, with no defects in development, life span or behaviors observed. The primary behavioral defect was that flies expressing either hTDP-43 G294A or M337V showed a faster decline with age in negative geotaxis. Together, these observations implied that neurons could handle these TDP-43 mutations by phosphorylation- and ubiquitin-dependent proteasome systems, even in a background without the wild type TDP-43. Our findings suggest that these two specific TDP-43 mutations are not inherently toxic, but may require additional environmental or genetic factors to affect longevity or survival. © 2017 Chang, Morton. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/161186
ISSN: 19326203
DOI: 10.1371/journal.pone.0180828
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