The dual functions of the extreme N-terminus of TDP-43 in regulating its biological activity and inclusion formation

Yong Jie Zhang, Thomas Caulfield, Ya Fei Xu, Tania F. Gendron, Jaime Hubbard, Caroline Stetler, Hiroki Sasaguri, Ena C. Whitelaw, Shuyi Cai, Wing Cheung Lee, Leonard Petrucelli

Research output: Contribution to journalArticlepeer-review

96 Scopus citations


TAR DNA-binding protein-43 (TDP-43) is the principal component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and the most common pathological subtype of frontotemporal dementia- frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP). To date, the C-terminus of TDP-43, which is aggregation-prone and contains almost all ALS-associated mutations, has garnered much attention while the functions of the N-terminus of TDP-43 remain largely unknown. To bridge this gap in our knowledge, we utilized novel cell culture and computer-assisted models to evaluate which region(s) of TDP- 43 regulate its folding, self-interaction, biological activity and aggregation. We determined that the extreme N-terminus of TDP-43, specifically the first 10 residues, regulates folding of TDP-43 monomers necessary for proper homodimerization and TDP-43-regulated splicing. Despite such beneficial functions, we discovered an interesting dichotomy: full-length TDP-43 aggregation, which is believed to be a pathogenic process, also requires the extreme N-terminus of TDP-43. As such, we provide new insight into the structural basis for TDP-43 function and aggregation, and we suggest that stabilization of TDP-43 homodimers, the physiologically active form of TDP-43, may be a promising therapeutic strategy for ALS and FTLD-TDP.

Original languageEnglish (US)
Pages (from-to)3112-3122
Number of pages11
JournalHuman molecular genetics
Issue number15
StatePublished - Aug 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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