In this review, the role of aberrant RNA metabolism in ALS is examined, including the evidence that a majority of the genetic mutations observed in familial ALS (including mutations in TDP-43, FUS/TLS, SOD1, angiogenin (ANG) and senataxin (SETX)) can impact directly on either gene transcription, pre-mRNA splicing, ribonucleoprotein complex formation, transport, RNA translation or degradation.
The study aims to understand if any of the rare ANG and RNASE4 variants catalogued in Project MinE consortium caused ALS due to loss of ribonucleolytic or nuclear translocation or both these activities.
We generated SH-SY5Y neuroblastoma cell lines constitutively expressing wild type (WT) Hemagglutinin (HA) epitope tagged mouse Ang1 (mAng1), and two amyotrophic lateral sclerosis associated ANG variants (C39W and K40I).
Recently, the angiogenin gene has been reported to be significantly associated with Parkinson's disease and amyotrophic lateral sclerosis in populations of European and American ancestry.
Our study thus highlights the strength of MD simulation-based predictions, and suggests that this method can be used for correlating mutations in Angiogenin or other effector proteins with ALS symptoms.
Variations in the coding and regulatory sequences of the angiogenin (ANG) gene are not associated to ALS (amyotrophic lateral sclerosis) in the Italian population.
Mutations in angiogenin (ANG), a member of the ribonuclease A superfamily, are associated with amyotrophic lateral sclerosis (ALS; sporadic and familial) and Parkinson's disease.
Our studies on the biochemical and structural features of these ANG variants now form the basis for further investigations to determine their role(s) in ALS.
While rare ANG/RNASE5 variants have been previously shown to be ALS causative, it is not yet known if any of the reported rare RNASE4 variants can also trigger ALS.
Our findings show that ANG plays an important role in neurite extension/pathfinding and survival providing a causal link between mutations in hANG and ALS.
Our results provide further evidence of a tight link between angiogenesis and ALS pathogenesis and suggest that mutations in ANG gene are associated with an increased risk to develop ALS.
Our studies on the biochemical and structural features of these ANG variants now form the basis for further investigations to determine their role(s) in ALS.
These predictions hold true, without exception, for all ANG mutants studied and can be employed to infer whether a new ANG mutation is causative of ALS or benign ahead of experimental findings.