The dual functions of the extreme N-terminus of TDP-43 in regulating its biological activity and inclusion formation.
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.
Mesh Terms:
Amyotrophic Lateral Sclerosis, DNA-Binding Proteins, Frontotemporal Dementia, Humans, Inclusion Bodies, Models, Anatomic, Protein Conformation, Protein Folding, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Stability, RNA Splicing
Amyotrophic Lateral Sclerosis, DNA-Binding Proteins, Frontotemporal Dementia, Humans, Inclusion Bodies, Models, Anatomic, Protein Conformation, Protein Folding, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Stability, RNA Splicing
Hum Mol Genet
Date: Aug. 01, 2013
PubMed ID: 23575225
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