Regardless, the recent finding that additional RNA-binding proteins may also cause ALS, and the observation that TDP-43 aggregation remains a core feature in all of the recently identified genetic forms of ALS (C9ORF72, VCP, UBQLN2, and PFN1), underscores the central role of TDP-43 and RNA metabolism in ALS and FTLD.
Given this genetic interaction and recent evidence linking stress granule dynamics to ALS pathogenesis, we hypothesized that profilin 1 might also associate with stress granules.
Impaired actin binding is a common denominator of several PFN1 mutations associated with amyotrophic lateral sclerosis, although further mechanisms may also contribute to the death of motor neurons.
PFN1 is a small actin-binding protein that promotes formin-based actin polymerization and regulates numerous cellular functions, but how the mutations in PFN1 cause ALS is unclear.
Here, we combine a screen of a new cohort of 383 ALS patients with multiple-sequence datasets to refine estimates of the ALS and FTD risk associated with PFN1E117G.
No mutations were identified in our cohort suggesting that PFN1 gene mutations are a very rare cause of familial ALS among patients with predominantly European ancestry.