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.
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Science, Beijing, China.
authors.forename: Weirui
authors.initials: W
authors.lastname: Guo
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhou
authors.forename: Amar
authors.initials: A
authors.lastname: Kar
authors.forename: Payal
authors.initials: P
authors.lastname: Ray
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Rao
authors.forename: Mengxue
authors.initials: M
authors.lastname: Yang
authors.forename: Haihong
authors.initials: H
authors.lastname: Ye
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Jianghong
authors.initials: J
authors.lastname: Liu
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.forename: Yanlian
authors.initials: Y
authors.lastname: Yang
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: David
authors.initials: D
authors.lastname: Zhang
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.forename: Marsel
authors.initials: M
authors.lastname: Mesulam
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.forename: Qi
authors.initials: Q
authors.lastname: Xu
authors.forename: Kazuo
authors.initials: K
authors.lastname: Fushimi
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Wu
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011328:Prions / Q000737:chemistry; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein
chemical_list: D004268:DNA-Binding Proteins; D011328:Prions