Using ALS to understand profilin 1's diverse roles in cellular physiology.

Profilin is an actin monomer-binding protein whose role in actin polymerization has been studied for nearly 50 years. While its principal biochemical features are now well understood, many questions remain about how profilin controls diverse processes within the cell. Dysregulation of profilin has been implicated in a broad range of human diseases, including neurodegeneration, inflammatory disorders, cardiac disease, and cancer. For example, mutations in the profilin 1 gene (PFN1) can cause amyotrophic lateral sclerosis (ALS), although the precise mechanisms that drive neurodegeneration remain unclear. While initial work suggested proteostasis and actin cytoskeleton defects as the main pathological pathways, multiple novel functions for PFN1 have since been discovered that may also contribute to ALS, including the regulation of nucleocytoplasmic transport, stress granules, mitochondria, and microtubules. Here, we will review these newly discovered roles for PFN1, speculate on their contribution to ALS, and discuss how defects in actin can contribute to these processes. By understanding profilin 1's involvement in ALS pathogenesis, we hope to gain insight into this functionally complex protein with significant influence over cellular physiology.