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.
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.
In summary, we conclude that genetic variations in UBQLN2 and PFN1 in a predominantly Flanders-Belgian cohort of FTLD and ALS patients are extremely rare.
Because of the considerable overlap between ALS and the common subtype of frontotemporal dementia, which is characterized by transactive response DNA-binding protein 43 pathology (FTLD-TDP), we tested cohorts of ALS and FTLD-TDP patients for PFN1 mutations.
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.
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.
In this study we show that expression of the ALS-associated actin-binding deficient mutant of PFN1 (PFN1(C71G)) results in increased dendritic arborisation and spine formation, and cytoplasmic inclusions in cultured mouse hippocampal neurons.
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.
Biophysical analysis of three novel profilin-1 variants associated with amyotrophic lateral sclerosis indicates a correlation between their aggregation propensity and the structural features of their globular state.