Dysregulation of TDP-43 intracellular localization and early onset ALS are associated with a TARDBP S375G variant

Kathy Newell, Francesca Paron, Miguel Mompean, Jill Murrell, Elisa Salis, Cristiana Stuani, Gary Pattee, Maurizio Romano, Douglas Laurents, Bernardino Ghetti, Emanuele Buratti

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


We investigated the Central Nervous System (CNS) and skeletal muscle tissue from A woman was clinically diagnosed with amyotrophic lateral sclerosis (ALS) at the age of 22. Neuropathologic evaluation showed upper and lower motor neuron loss, corticospinal tract degeneration and skeletal muscle denervation. Analysis of the patient's Deoxyribonucleic acid (DNA) revealed a AGT>GGT change resulting in an S375G substitution in the C-terminal region of TDP-43. This variant was previously reported as being benign. Considering the early onset and severity of the disease in this patient, we tested the effects of this genetic variant on TDP-43 localization, pre-mRNA splicing activity and toxicity, in parallel with the effects on known neighboring disease-associated mutations. In cell lines, expressed in culture, S375G TDP-43 appeared to be more significantly localized in the nucleus and to exert higher toxicity than wild-type TDP-43. Strikingly, a phosphomimic mutant at the same residue (S375E) showed a strong tendency to accumulate in the cytoplasm, especially under stress conditions, and molecular dynamics simulations suggest that phosphorylation of this residue can disrupt TDP-43 intermolecular interactions. The results of the current study highlight the importance of phosphorylation and regulation of TDP-43 nuclear-cytoplasmic shuttling/redistribution, in relation to the pathogenetic mechanisms involved in different forms of ALS.

Original languageEnglish (US)
Pages (from-to)397-413
Number of pages17
JournalBrain Pathology
Issue number3
StatePublished - May 2019


  • ALS
  • FTLD
  • TARDBP mutations
  • TDP-43 mutations
  • mRNA splicing
  • neurodegeneration
  • phosphorylation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neuroscience(all)
  • Clinical Neurology

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