Poster Presentation 2014 International Biophysics Congress

An ALS-mutant TDP-43 neurotoxic peptide adopts an anti-parallel β-structure and induces TDP-43 redistribution (#538)

Li Zhu 1 , Meng Xu 2 , Mengxue Yang 1 , Yanlian Yang 2 , Yang Li 3 , Jianwen Deng 1 , Linhao Ruan 1 , Jianghong Liu 1 , Sidan Du 3 , Xuehui Liu 1 , Wei Feng 1 , Kazuo Fushimi 4 , Eileen H. Bigio 5 , Marsel Mesulam 5 , Chen Wang 2 , Jane Y. Wu 4
  1. Institute of Biophysics, CAS, Beijing, China
  2. National Center for Nanoscience and Technology, Beijing, China
  3. School of Electronic Science and Engineering, Nanjing University, Nanjing, China
  4. Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
  5. The Cognitive Neurology & Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

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. AFM and EM 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 amyloid-β peptide. Sequential Nuclear Overhauser Effects (NOEs) and Double-quantum-filtered correlation spectroscopy (DQF-COSY) in NMR analyses of the A315E-mutant TDP-43 peptide indicate that it adopts an anti-parallel β conformation. Neuronal cultures in compartmentalized microfluidic-chambers demonstrate that the TDP-43 peptides can be taken up by axons and induce TDP-43 redistribution, axonotoxicity and neuronal death, thus, recapitulating key neuropathological features of TDP-43 proteinopathies. Importantly, one 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.