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

作者：Guo, Weirui; Chen, Yanbo; Zhou, Xiaohong; Kar, Amar; Ray, Payal; Chen, Xiaoping; Rao, Elizabeth J.; Yang, Mengxue; Ye, Haihong; Zhu, Li; Liu, Jianghong; Xu, Meng; Yang, Yanlian; Wang, Chen; Zhang, David; Bigio, Eileen H.; Mesulam, Marsel; Shen, Yan; Xu, Qi^*; Fushimi, Kazuo; Wu, Jane Y.

来源：Nature Structural & Molecular Biology, 2011, 18(7): 822-U102.

DOI：10.1038/nsmb.2053

• AMYOTROPHIC-LATERAL-SCLEROSIS
• FRONTOTEMPORAL LOBAR DEGENERATION
• TRANSGENIC MICE
• FUNCTIONAL IMPLICATIONS
• CELLULAR TOXICITY
• GENE
• INCLUSIONS
• YEAST
• NEURODEGENERATION
• PHOSPHORYLATION

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.

• 出版日期2011-7
• 单位脑与认知科学国家重点实验室; 中国科学院; 中国医学科学院北京协和医院; 西北大学; 国家纳米科学中心; 北京协和医学院