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.
This report confirms that clinical course of SOD1-related ALS may be modulated by other causative or associated genes, including ANG and suggests that extensive screening of ALS-associated genes in patients with an already identified mutation may be helpful for better knowledge of genetic architecture of ALS.
Through these case studies, the construction and analyses of a PPI network for angiogenin protein in amyotrophic lateral sclerosis, a signal-gene-protein interaction network for presenilin protein in Alzheimer's disease and a Boolean network for a mammalian cell cycle was demonstrated.
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.
In a mouse model of amyotrophic lateral sclerosis and in preliminary clinical trials in patients with amyotrophic lateral sclerosis, the combined administration of recombinant adenoviral vectors (Ad5-VEGF+Ad5-ANG) encoding the neurotrophic/angiogenic factors vascular endothelial growth factor ( VEGF) and angiogenin ( ANG) was found to slow the development of neurological deficits.
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.
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.
Identification of mutations in other genes that cause ALS/FTD, such as C9ORF72, sentaxin, and angiogenin, lends support to the idea that defective RNA metabolism is a critical pathogenic pathway.
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.
By differentiating between the two dichotomous biological activities of ANG, this strategy could provide a viable pharmacological approach for the treatment of 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.
Mutations in many of these RBPs are associated with neurological diseases, including FMRP in fragile X syndrome; TDP-43, FUS (fused in sarcoma), angiogenin, and ataxin-2 in amyotrophic lateral sclerosis; ataxin-2 in spinocerebellar ataxia; and SMN (survival of motor neuron protein) in spinal muscular atrophy.
When yeast genetic interaction partners held in common between human OPTN and ANG were validated in mammalian cells and zebrafish, MAP2K5 kinase emerged as a potential drug target for ALS therapy.
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.
Overall, these findings identify angiogenin as a novel candidate gene in the pathogenesis of ALS--a discovery that ultimately might lead to the development of new therapeutic strategies.