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Structural basis for mutation-induced destabilization of profilin 1 in ALS

Significance Mutations in profilin 1 (PFN1) were recently shown to cause amyotrophic lateral sclerosis (ALS); however, little is known about the pathological mechanism of PFN1 in disease. We demonstrate that ALS-linked mutations cause PFN1 to become destabilized in vitro and in cells, likely through a mechanism that involves mutation-induced cavities within the protein core. Changes in protein stability due to disease-causing mutations can play a pivotal role across different disease mechanisms. The destabilized mutant-PFN1 species identified here can serve as an upstream trigger for either loss-of-function or gain-of-toxic-function mechanisms and thus emerges from these studies as a pertinent therapeutic target for the incurable disease ALS. Mutations in profilin 1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS); however, the pathological mechanism of PFN1 in this fatal disease is unknown. We demonstrate that ALS-linked mutations severely destabilize the native conformation of PFN1 in vitro and cause accelerated turnover of the PFN1 protein in cells. This mutation-induced destabilization can account for the high propensity of ALS-linked variants to aggregate and also provides rationale for their reported loss-of-function phenotypes in cell-based assays. The source of this destabilization is illuminated by the X-ray crystal structures of several PFN1 proteins, revealing an expanded cavity near the protein core of the destabilized M114T variant. In contrast, the E117G mutation only modestly perturbs the structure and stability of PFN1, an observation that reconciles the occurrence of this mutation in the control population. These findings suggest that a destabilized form of PFN1 underlies PFN1-mediated ALS pathogenesis.