@article{d8247945c1f94efc8a781015dd83b9e9,
title = "An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity",
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.",
author = "Weirui Guo and Yanbo Chen and Xiaohong Zhou and Amar Kar and Payal Ray and Xiaoping Chen and Rao, {Elizabeth J.} and Mengxue Yang and Haihong Ye and Li Zhu and Jianghong Liu and Meng Xu and Yanlian Yang and Chen Wang and David Zhang and Bigio, {Eileen H.} and Marsel Mesulam and Yan Shen and Qi Xu and Kazuo Fushimi and Wu, {Jane Y.}",
note = "Funding Information: We thank F. Baralle, E. Buratti, B. Cui, D. Kuo, N. Jayaram, Y. Li, M. Mishra, S. Perrett, M.-Y. Shen, M.-J. Zhang and T. Siddique for providing invaluable suggestions and reagents and for critical reading of the manuscript. We thank members of the Wu laboratory for stimulating discussions and suggestions. We thank L. Guo and L. Wang for technical assistance and A. Joselin for help in the early stage of the work. W.G. (grant 2009CB825402) and Y.C., H.Y. and Q.X. (grant 2010CB529603) are supported by the Ministry of Science and Technology (MOST) China 973 Project . J.Y.W. is supported by funds from Northwestern University and the Chinese Academy of Science (CAS). Y.Y. and C.W. are supported by CAS and MOST. We also thank the US National Institutes of Health (grant AG13854 to M.M. and E.H.B.) for support.",
year = "2011",
month = jul,
doi = "10.1038/nsmb.2053",
language = "English (US)",
volume = "18",
pages = "822--831",
journal = "Nature Structural and Molecular Biology",
issn = "1545-9993",
publisher = "Nature Publishing Group",
number = "7",
}