title: The dual functions of the extreme N-terminus of TDP-43 in regulating its biological activity and inclusion formation.
abstract: 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.
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Thomas
authors.initials: T
authors.lastname: Caulfield
authors.forename: Ya-Fei
authors.initials: YF
authors.lastname: Xu
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.forename: Jaime
authors.initials: J
authors.lastname: Hubbard
authors.forename: Caroline
authors.initials: C
authors.lastname: Stetler
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasaguri
authors.forename: Ena C
authors.initials: EC
authors.lastname: Whitelaw
authors.forename: Shuyi
authors.initials: S
authors.lastname: Cai
authors.forename: Wing Cheung
authors.initials: WC
authors.lastname: Lee
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D008953:Models, Anatomic; D011487:Protein Conformation; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D055550:Protein Stability; D012326:RNA Splicing
chemical_list: D004268:DNA-Binding Proteins