title: Induction of amyloid fibrils by the C-terminal fragments of TDP-43 in amyotrophic lateral sclerosis.
abstract: TAR DNA-binding protein 43 (TDP-43) has been identified as the major ubiquitinated aggregates in the inclusion bodies in the patients of amyotrophic lateral sclerosis (ALS) since 2006 and become a crucial culprit for ALS and related motor neuron diseases. Recent literature has further indicated that the major components of these aggregates are hyper-phosphorylated TDP-43 C-terminus. In an effort to clarify the conformational and physical properties of its disordered C-terminal domain, we have synthesized several peptide fragments and shown that only D1 within D1-4 can form twisted fibrils with a cross section of approximately 11 nm in width under the incubation of phosphate buffer. In contrast, the D2-4 peptides all formed amorphous aggregates, showing different aggregation propensities. In addition to D1, two pathological mutant peptides, A315T and G294A, can also form fibrils that share similar shape and morphology with neuronal cytoplasmic inclusions. We propose that the residues with this region (287-322), which contains myriads of glycine repeats, may contribute significantly to the fiber formation as well as aggregation propensity. Moreover, from the conformational characterizations of D1, A315T, and G294A with EM, CD, fluorescence, and Raman spectroscopy, we found that all three peptides formed an amyloid structure, providing insights into the nature of its aggregation vis a vis the other fragments in the C-terminus of TDP-43.
authors.affiliation: Institute of Chemistry, Academia Sinica, No. 128, Sec 2, Academia Road, Nankang, Taiwan, ROC.
authors.forename: Allan K-H
authors.initials: AK
authors.lastname: Chen
authors.forename: Ryan Y-Y
authors.initials: RY
authors.lastname: Lin
authors.forename: Eva Z-J
authors.initials: EZ
authors.lastname: Hsieh
authors.forename: Pang-Hsien
authors.initials: PH
authors.lastname: Tu
authors.forename: Rita P-Y
authors.initials: RP
authors.lastname: Chen
authors.forename: Tai-Yan
authors.initials: TY
authors.lastname: Liao
authors.forename: Wenlung
authors.initials: W
authors.lastname: Chen
authors.forename: Chih-Hsien
authors.initials: CH
authors.lastname: Wang
authors.forename: Joseph J-T
authors.initials: JJ
authors.lastname: Huang
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D000682:Amyloid; D004268:DNA-Binding Proteins; D010446:Peptide Fragments