IP-MS of ALS-linked PFN1 variants

Dominant mutations in profilin-1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by motor neuron loss, paralysis, and death from respiratory failure. Our lab recently demonstrated that PFN1 mutant proteins are destabilized—they unfold at milder conditions during thermal and chemical denaturation. Furthermore, we and others have shown that mutant PFN1 is more prone to misfold and aggregate. This misfolding alters the protein-protein interactions of PFN1, as demonstrated by an immunoprecipitation-mass spectrometry (IP-MS) screen of wild-type and ALS-associated PFN1 variants. While ALS-associated mutants do not show loss of interaction, several variants have altered interactions with one or several formin family proteins, a group of proteins that interact with profilins to regulate actin polymerization.