Profilin-1 (PFN1) and TDP-43 are two proteins that have been linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We have used a combination of NMR spectroscopy and molecular dynamics (MD) simulation to characterize their structure and dynamics in solution. We observed that two ALS-linked mutations of PFN1, G1118V and M114T, impact the internal dynamics of the protein, and therefore have the potential to impact the interaction of PFN1 with its binding partners actin and formin. For TDP-43, we have identified a core nucleus of structure for a folding intermediate in its second RNA recognition motif (RRM2). Our studies suggest a role for this RRM2 intermediate in normal TDP-43 function as well as in dysfunction by serving as a template for misfolding, aberrant interactions and aggregation.