Chen Wang

Publications (2)16.12 Total impact

• Article: Characterization of β-domains in C-terminal fragments of TDP-43 by scanning tunneling microscopy.

  Meng Xu, Li Zhu, Jianghong Liu, Yanlian Yang, Jane Y Wu, Chen Wang
  [show abstract] [hide abstract]
  ABSTRACT: The TAR DNA-binding protein 43 (TDP-43) has been identified as a critical player in a range of neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Recent discoveries demonstrate the important role of carboxyl-terminal fragments of TDP-43 in its proteinopathy. Herein, we report the characterization of β-domains in the C-terminal fragments of TDP-43 using scanning tunneling microscopy (STM). Careful comparison of the wild-type TDP-43 (Wt) and the three mutant TDP-43 peptides: an ALS-related mutant peptide: phosphorylated A315T mutant TDP-43 (A315T(p)) and two model peptides: A315T mutant TDP-43 (A315T), A315E mutant TDP-43 (A315E) reveals that A315T(p) has a longer core region of the β-domain than Wt. A315E possesses the longest core region of the β-domain and A315T(p) mutant TDP-43 has the second longest core region of the β-domain. The core regions of the β-domains for A315T and Wt TDP-43 have the same length. This observation provides a supportive evidence of a higher tendency in beta-sheet formation of A315T(p) containing TDP-43 fragment, and structural mechanism for the higher cytotoxicity and accelerated fibril formation of the A315T(p) mutation-containing TDP-43 peptide as compared with Wt TDP-43.
  Journal of Structural Biology 11/2012; · 3.41 Impact Factor
• Source

  Available from: Kazuo Fushimi

  Article: An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity.

  Weirui Guo, Yanbo Chen, Xiaohong Zhou, Amar Kar, Payal Ray, Xiaoping Chen, Elizabeth J Rao, Mengxue Yang, Haihong Ye, Li Zhu, [......], Meng Xu, Yanlian Yang, Chen Wang, David Zhang, Eileen H Bigio, Marsel Mesulam, Yan Shen, Qi Xu, Kazuo Fushimi, Jane Y Wu
  [show abstract] [hide abstract]
  ABSTRACT: Mutations in TARDBP, encoding TAR DNA-binding protein-43 (TDP-43), are associated with TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We compared wild-type TDP-43 and an ALS-associated mutant TDP-43 in vitro and in vivo. The A315T mutant enhances neurotoxicity and the formation of aberrant TDP-43 species, including protease-resistant fragments. The C terminus of TDP-43 shows sequence similarity to prion proteins. Synthetic peptides flanking residue 315 form amyloid fibrils in vitro and cause neuronal death in primary cultures. These data provide evidence for biochemical similarities between TDP-43 and prion proteins, raising the possibility that TDP-43 derivatives may cause spreading of the disease phenotype among neighboring neurons. Our work also suggests that decreasing the abundance of neurotoxic TDP-43 species, enhancing degradation or clearance of such TDP-43 derivatives and blocking the spread of the disease phenotype may have therapeutic potential for TDP-43 proteinopathies.
  Nature Structural &#38 Molecular Biology 06/2011; 18(7):822-30. · 12.71 Impact Factor