title: An ALS-mutant TDP-43 neurotoxic peptide adopts an anti-parallel β-structure and induces TDP-43 redistribution.
abstract: 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-β 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 β 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.
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: National Center for Nanoscience and Technology, Beijing, China Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China and.
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.affiliation: 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 of Medicine, Chicago, USA.
authors.forename: Mengxue
authors.initials: M
authors.lastname: Yang
authors.affiliation: National Center for Nanoscience and Technology, Beijing, China.
authors.forename: Yanlian
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Deng
authors.affiliation: 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.
authors.forename: Linhao
authors.initials: L
authors.lastname: Ruan
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jianghong
authors.initials: J
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Sidan
authors.initials: S
authors.lastname: Du
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xuehui
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.affiliation: Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, USA.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Fushimi
authors.affiliation: The Cognitive Neurology & Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago, Chicago, IL 60611, USA.
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.affiliation: The Cognitive Neurology & Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago, Chicago, IL 60611, USA.
authors.forename: Marsel
authors.initials: M
authors.lastname: Mesulam
authors.affiliation: National Center for Nanoscience and Technology, Beijing, China wangch@nanoctr.cn jane-wu@northwestern.edu.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: 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@northwestern.edu.
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Wu
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D057809:HEK293 Cells; D006801:Humans; D046210:Microfluidic Analytical Techniques; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D057177:TDP-43 Proteinopathies / Q000378:metabolism* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D004268:DNA-Binding Proteins
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