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

• DOI: 10.1038/nsmb.2053
• Publication Date: 2011-06-12T17:58:36Z
• Authors: Weirui Guo; Yanbo Chen; Xiaohong Zhou; Amar Kar; Payal Ray; Xiaoping Chen; Elizabeth J Rao; Mengxue Yang; Haihong Ye; Li Zhu; Jianghong Liu; Meng Xu; Yanlian Yang; Chen Wang; David Zhang; Eileen H Bigio; Marsel Mesulam; Yan Shen; Qi Xu; Kazuo Fushimi; Jane Y Wu
• Keywords: 0301 basic medicine; Prions; Amyotrophic Lateral Sclerosis; Molecular Sequence Data; Protein Structure, Secondary; Protein Structure, Tertiary; DNA-Binding Proteins; 03 medical and health sciences; Amino Acid Substitution; Sequence Analysis, Protein; Mutation; Humans; Amino Acid Sequence; Sequence Alignment; Cells, Cultured

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.