Protein Aggregation and Pore-Formation of a Neurodegenerative Protein Fragment

Neurodegenerative diseases are often associated with protein aggregates, but the molecular mechanism of cytotoxicity remains ambiguous. Transactive response DNA binding protein (TDP-43) is the major component of neuronal inclusion bodies of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Amyloid deposits of TDP-43 can accumulate at the intracellular and extracellular spaces in the central nervous system, leading to neurodegenerative disease. Using unbiased atomic-detail molecular dynamics simulations, we explored the aggregation of C-terminal fragments of TDP-43, which have been suggested to form membrane pores, in the presence of lipid bilayer membranes. The peptides were found to aggregate and form disordered-toroidal pores in a lipid bilayer membrane. The cytotoxicity of TDP-43 can be inferred from the observation that the membrane pores conduct water and ions at high rates. The disordered nature of the pore catalyzes lipid flip-flop between bilayer leaflets and suggests that TDP-43 is able to cross the membrane spontaneously, explaining why the peptide is present both in the cytosol and the extracellular matrix in neurodegenerative disease.