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

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• TDP-43 proteinopathies, including FTLD-TDP and ALS, were historically distinct from classical amyloid diseases.
• The role of TDP-43 aggregation in neurodegeneration is increasingly recognized.
• Structural similarities between TDP-43 and amyloid proteins remain underexplored.

Purpose of the Study:

• To investigate the structural characteristics of TDP-43 peptides.
• To determine if TDP-43 peptides can form amyloid fibrils.
• To explore the neurotoxic mechanisms of TDP-43 amyloidogenesis.

Main Methods:

• Atomic force microscopy (AFM) and electron microscopy (EM) for fibril structure analysis.
• Nuclear magnetic resonance (NMR) spectroscopy (sNOE, DQ-filtered COSY) for conformational studies.
• Cell culture and microfluidic chambers to assess TDP-43 peptide uptake, toxicity, and cellular effects.

Main Results:

• TDP-43 peptides form amyloid fibrils with a core structure similar to those found in FTLD-TDP brain tissue.
• An ALS-linked TDP-43 mutant peptide (A315E) can cross-seed other TDP-43 peptides and amyloid-beta.
• NMR revealed an anti-parallel beta-conformation for the A315E TDP-43 peptide.
• Amyloidogenic TDP-43 peptides induce TDP-43 nuclear-to-cytoplasmic redistribution and axonotoxicity in neuronal cultures.
• Disruption of fibril formation by a single amino acid change abolished neurotoxicity.

Conclusions:

• TDP-43 peptides can form amyloid structures, linking TDP-43 proteinopathies to amyloid diseases.
• Amyloidogenesis of TDP-43 is critical for its neurotoxic effects, including axonotoxicity and neuronal death.
• These findings provide a molecular basis for TDP-43 neurotoxicity and suggest therapeutic targets.