Your browser doesn't support javascript.
loading
An ALS-mutant TDP-43 neurotoxic peptide adopts an anti-parallel ß-structure and induces TDP-43 redistribution.
Zhu, Li; Xu, Meng; Yang, Mengxue; Yang, Yanlian; Li, Yang; Deng, Jianwen; Ruan, Linhao; Liu, Jianghong; Du, Sidan; Liu, Xuehui; Feng, Wei; Fushimi, Kazuo; Bigio, Eileen H; Mesulam, Marsel; Wang, Chen; Wu, Jane Y.
Affiliation
  • Zhu L; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • Xu M; National Center for Nanoscience and Technology, Beijing, China Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China and.
  • Yang M; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China University of the Chinese Academy of Sciences, Beijing, China Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School o
  • Yang Y; National Center for Nanoscience and Technology, Beijing, China.
  • Li Y; School of Electronic Science and Engineering, Nanjing University, Nanjing, China Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, USA.
  • Deng J; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China University of the Chinese Academy of Sciences, Beijing, China.
  • Ruan L; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China University of the Chinese Academy of Sciences, Beijing, China.
  • Liu J; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • Du S; School of Electronic Science and Engineering, Nanjing University, Nanjing, China Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, USA.
  • Liu X; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • Feng W; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • Fushimi K; Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, USA.
  • Bigio EH; The Cognitive Neurology & Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago, Chicago, IL 60611, USA.
  • Mesulam M; The Cognitive Neurology & Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago, Chicago, IL 60611, USA.
  • Wang C; National Center for Nanoscience and Technology, Beijing, China wangch@nanoctr.cn jane-wu@northwestern.edu.
  • Wu JY; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, USA wangch@nanoctr.cn jane-wu@northwester
Hum Mol Genet ; 23(25): 6863-77, 2014 Dec 20.
Article in En | MEDLINE | ID: mdl-25113748
TDP-43 proteinopathies are clinically and genetically heterogeneous diseases that had been considered distinct from classical amyloid diseases. Here, we provide evidence for the structural similarity between TDP-43 peptides and other amyloid proteins. Atomic force microscopy and electron microscopy examination of peptides spanning a previously defined amyloidogenic fragment revealed a minimal core region that forms amyloid fibrils similar to the TDP-43 fibrils detected in FTLD-TDP brain tissues. An ALS-mutant A315E amyloidogenic TDP-43 peptide is capable of cross-seeding other TDP-43 peptides and an amyloid-ß peptide. Sequential Nuclear Overhauser Effects and double-quantum-filtered correlation spectroscopy in nuclear magnetic resonance (NMR) analyses of the A315E-mutant TDP-43 peptide indicate that it adopts an anti-parallel ß conformation. When added to cell cultures, the amyloidogenic TDP-43 peptides induce TDP-43 redistribution from the nucleus to the cytoplasm. Neuronal cultures in compartmentalized microfluidic-chambers demonstrate that the TDP-43 peptides can be taken up by axons and induce axonotoxicity and neuronal death, thus recapitulating key neuropathological features of TDP-43 proteinopathies. Importantly, a single amino acid change in the amyloidogenic TDP-43 peptide that disrupts fibril formation also eliminates neurotoxicity, supporting that amyloidogenesis is critical for TDP-43 neurotoxicity.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cerebral Cortex / Amyloid beta-Peptides / DNA-Binding Proteins / TDP-43 Proteinopathies / Neurons Limits: Animals / Humans Language: En Journal: Hum Mol Genet Journal subject: BIOLOGIA MOLECULAR / GENETICA MEDICA Year: 2014 Document type: Article Affiliation country: China Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cerebral Cortex / Amyloid beta-Peptides / DNA-Binding Proteins / TDP-43 Proteinopathies / Neurons Limits: Animals / Humans Language: En Journal: Hum Mol Genet Journal subject: BIOLOGIA MOLECULAR / GENETICA MEDICA Year: 2014 Document type: Article Affiliation country: China Country of publication: United kingdom