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.
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.
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.
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.
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.
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.
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.
Knockdown of endogenous Drosophila PFN1 did not alter the degenerative phenotypes of the retina in flies overexpressing wild-type TDP-43 These data suggest that ALS-linked PFN1 mutations exacerbate TDP-43-induced neurodegeneration in a gain-of-function manner, possibly by shifting the localization of TDP-43 from nuclei to cytoplasm.