The crystal structures of multiple metagenome-derived single-stranded RNA (ssRNA) bacteriophages are published in Science Advances this week, providing new insights into this group of small bacterial viruses. Metagenomic sequencing efforts have uncovered an immense number of distinct uncultured ssRNA phages, yet little is known about the structure, host bacteria, lysis strategies, and other essential characteristics of these newly discovered life forms. To address this knowledge gap, scientists from the Latvian Biomedical Research and Study Center recombinantly expressed metagenome-derived ssRNA phage coat proteins (CPs) to produce virus-like particles and determined the three-dimensional structure of 22 previously uncharacterized ssRNA phage capsids covering nine distinct CP types. They find substantial deviations from the previously known ssRNA phage CP fold, uncover an unusual prolate particle shape, and reveal a previously unseen dsRNA binding mode.
Gene-silencing antisense oligonucleotides (ASOs) targeting a gene involved in many cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) may help reduce the pathogenic accumulation of a protein that is a hallmark of the two neurodegenerative disorders. G4C2 repeat expansions in the C9orf72 gene are the most common causes of ALS and FTD, which frequently feature the buildup of TAR DNA-binding protein 43 (TDP-43) in the brains of patients. As reported in Science Translational Medicine this week, a Mayo Clinic-led team found that a poly glycine-arginine protein [poly(GR)] produced by the C9orf72 repeat expansion enhanced the formation of TDP-43 in vitro and in mice by altering nucleocytoplasmic transport. Treating the mice with poly(GR)-targeting ASOs, meanwhile, reduced aggregation of TDP-43 aggregation and protected neurons from damage. In addition to establishing a mechanistic link between the C9orf72 repeat expansion and TDP-43 proteinopathy, the study highlights the potential of G4C2-targeting drugs.