Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis

Life Sci Alliance. 2019 Sep 16;2(5):e201900358. doi: 10.26508/lsa.201900358. Print 2019 Oct.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation
  • Gene Knockout Techniques
  • Genetic Pleiotropy
  • HeLa Cells
  • Homeostasis
  • Humans
  • Mutation
  • Nuclear Pore Complex Proteins / genetics*
  • Organelles / metabolism*
  • RNA Transport


  • DNA-Binding Proteins
  • NUP188 protein, human
  • Nuclear Pore Complex Proteins
  • TARDBP protein, human