Cellular stress is a major cause of neurodegenerative diseases. In particular, in amyotrophic lateral sclerosis (ALS), around 90% of the cases are believed to occur due to aggregation and misfolding of TDP-43 protein in neurons due to aging and chronic environmental stress. However, the physicochemical basis of how TDP-43 senses the change in solvation conditions during stress and misfolds remains very poorly understood. We show here that the full-length human TDP-43 can exist in equilibrium with multiple structural states. The equilibrium between these states is highly sensitive to changes in solvation conditions. We show that upon thermal and pH stress, amyloidogenic oligomers can form amyloid-like fibrils. However, the internal structure of the fibril depends upon the physicochemical nature of stress. Our results present a physical basis of the effect of solvation conditions on inter- and intramolecular assembly formation of TDP-43 and reconcile why the nature and the internal structure of the aggregated form have been found to be different when extracted from the brain of different ALS patients.

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