Structural transformation of the amyloidogenic core region of TDP-43 protein initiates its aggregation and cytoplasmic inclusion

Lei Lei Jiang, Mei Xia Che, Jian Zhao, Chen Jie Zhou, Mu Yun Xie, Hai Yin Li, Jian Hua He, Hong Yu Hu

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

TDP-43 (TAR DNA-binding protein of 43 kDa) is a major deposited protein in amyotrophic lateral sclerosis and frontotemporal dementia with ubiquitin. A great number of genetic mutations identified in the flexible C-terminal region are associated with disease pathologies. We investigated the molecular determinants of TDP-43 aggregation and its underlying mechanisms. We identified a hydrophobic patch (residues 318-343) as the amyloidogenic core essential for TDP-43 aggregation. Biophysical studies demonstrated that the homologous peptide formed a helix-turn-helix structure in solution, whereas it underwent structural transformation from an α-helix to a β-sheet during aggregation. Mutation or deletion of this core region significantly reduced the aggregation and cytoplasmic inclusions of full-length TDP-43 (or TDP-35 fragment) in cells. Thus, structural transformation of the amyloidogenic core initiates the aggregation and cytoplasmic inclusion formation of TDP-43. This particular core region provides a potential therapeutic target to design small-molecule compounds for mitigating TDP-43 proteinopathies.

Original languageEnglish (US)
Pages (from-to)19614-19624
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number27
DOIs
StatePublished - Jul 5 2013

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