title: The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies.
abstract: The degraded, misfolded C terminus of TAR DNA-binding protein-43 is associated with a wide spectrum of neurodegenerative diseases, particularly frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. However, the precise mechanism of pathological cleavage of the TAR DNA-binding protein-43 remains unknown. Here we show that the TAR DNA-binding protein-43 C-terminal protein physically interacts with itself or with the cellular-folded yeast prion domain of Sup35 forming dynamic aggregates. This prion-like nature governs known cellular functions of the TAR DNA-binding protein-43, including subcellular localisation and exon skipping of the cystic fibrosis transmembrane conductance regulator. Significantly, mutants with a failure to engage in prion-like interactions are processed into an ~24-kDa C-terminal fragment of the TAR DNA-binding protein-43. The estimated cleavage site of degraded TAR DNA-binding protein-43 fragments corresponds to the pathological cleavage site identified in patients with the TAR DNA-binding protein-43 proteinopathies. Consistently, epigallocatechin gallate constrains prion-like interactions, attenuating pathological-like degradation. Thus, the native folding of TAR DNA-binding protein-43 C terminus acts as a guardian of pathogenesis, which is directly associated with loss-of-function.
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan. mirna125@gmail.com
authors.forename: I-Fan
authors.initials: IF
authors.lastname: Wang
authors.forename: Hsiang-Yu
authors.initials: HY
authors.lastname: Chang
authors.forename: Shin-Chen
authors.initials: SC
authors.lastname: Hou
authors.forename: Gunn-Guang
authors.initials: GG
authors.lastname: Liou
authors.forename: Tzong-Der
authors.initials: TD
authors.lastname: Way
authors.forename: C-K
authors.initials: CK
authors.lastname: James Shen
mesh_terms: D020816:Amino Acid Motifs; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005091:Exons; D006801:Humans; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis
chemical_list: D004268:DNA-Binding Proteins