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- Title
An ALS-mutant TDP-43 neurotoxic peptide adopts an anti-parallel β-structure and induces TDP-43 redistribution.
- Authors
Li Zhu; Meng Xu; Mengxue Yang; Yanlian Yang; Yang Li; Jianwen Deng; Linhao Ruan; Jianghong Liu; Sidan Du; Xuehui Liu; Wei Feng; Kazuo Fushimi; Eileen H. Bigio; Marsel Mesulam; Chen Wang; Jane Y. Wu
- 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-43fibrils detected in FTLD-TDP brain tissues. An ALS-mutant A315 E 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 b 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 theamyloidogenic TDP-43 peptide that disrupts fibril formation also eliminates neurotoxicity, supporting that amyloidogenesis is critical for TDP-43 neurotoxicity.
- Publication
Human Molecular Genetics, 2012, Vol 21, Issue 25, p1
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddu409