RT Journal Article
SR Electronic
T1 Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900358
DO 10.26508/lsa.201900358
VO 2
IS 5
A1 Agnes Roczniak-Ferguson
A1 Shawn M Ferguson
YR 2019
UL https://www.life-science-alliance.org/content/2/5/e201900358.abstract
AB TDP-43 is an RNA-binding protein that forms cytoplasmic aggregates in multiple neurodegenerative diseases. Although the loss of normal TDP-43 functions likely contributes to disease pathogenesis, the cell biological consequences of human TDP-43 depletion are not well understood. We, therefore, generated human TDP-43 knockout (KO) cells and subjected them to parallel cell biological and transcriptomic analyses. These efforts yielded three important discoveries. First, complete loss of TDP-43 resulted in widespread morphological defects related to multiple organelles, including Golgi, endosomes, lysosomes, mitochondria, and the nuclear envelope. Second, we identified a new role for TDP-43 in controlling mRNA splicing of Nup188 (nuclear pore protein). Third, analysis of multiple amyotrophic lateral sclerosis causing TDP-43 mutations revealed a broad ability to support splicing of TDP-43 target genes. However, as some TDP-43 disease-causing mutants failed to fully support the regulation of specific target transcripts, our results raise the possibility of mutation-specific loss-of-function contributions to disease pathology.