Molecular dynamics of dipeptide repeat proteins implicated in C9orf72 ALS/FTD at amino acid resolution

In our cells, there is a crucial transportation system called nucleocytoplasmic transport (NCT), allowing molecules to move between the nucleus and cytoplasm. In models of neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), this nuclear transport system is disrupted, causing the cells to deteriorate. This disruption can be caused by harmful proteins, named dipeptide repeat proteins (DPRs), resulting from a genetic mutation. The exact mechanism, however, remains unclear. Our study aims to understand the properties of DPRs and how they impact this vital transport process. The most significant findings of our study revolve around the interaction between poly-proline-arginine (polyPR), the most toxic DPR, and key components of nucleocytoplasmic transport (NCT). We used molecular dynamics models to show that polyPR does not bind permanently to the nuclear pore complex (NPC) but directly binds to multiple nuclear transport receptors, which are essential for the transport cycle. By identifying key binding sites, we propose a complete mechanical picture for polyPR-mediated NCT defects. The findings of our study advance our understanding of the role of DPRs in C9orf72-ALS/FTD, providing insights that may inform potential therapeutic strategies.