Production of poly(GA) in C9ORF72 patient motor neurons derived from induced pluripotent stem cells

GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A key pathological hallmark of C9ORF72-related ALS/FTD is the accumulation of dipeptide repeat (DPR) proteins synthesized from both sense and antisense repeat RNAs in affected neurons.To investigate how DPR proteins are synthesized in C9ORF72 human neurons, we used CRISPR-Cas9 technology to generate a homozygous deletion in the first intron of C9ORF72, 5′ to the G4C2 repeats to assess the effect of this deletion on DPR production

CRISPR deletion of the C9ORF72 promoter in ALS/FTD patient motor neurons abolishes production of dipeptide repeat proteins and rescues neurodegeneration

GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Brain tissues from affected individuals show characteristic nuclear RNA foci containing the expanded repeat RNAs, as well as neuronal inclusions containing dipeptide repeat (DPR) proteins [poly(GA), poly(GP), poly(GR), poly(PR), and poly(PA)] resulting from the translation of both sense and antisense repeat RNAs in all reading frames. Although reduced C9ORF72 protein function may contribute to disease, the more likely drivers of disease are mechanisms related to a gain of toxic function. Currently, intense efforts are being made to identify disease mechanisms amenable for the development of therapeutic strategies. One promising avenue would be to prevent the production of the expanded repeat RNAs, such as by antisense oligonucleotides. Here, we tested another potential therapeutic approach: CRISPR/Cas9-based targeting of the promoter region

Di-μ-benzoato-κ3 O,O′:O;κ3 O:O,O′-bis­[aqua­(nitrato-κO)(1,10-phenanthroline-κ2 N,N′)lead(II)]

The title compound, [Pb2(C7H5O2)2(NO3)2(C12H8N2)2(H2O)2], crystallizes as a dinuclear centrosymmetric dimer containing two PbII atoms bridged by two benzoate ligands. Each PbII atom is seven-coordinated by a water mol­ecule, a nitrate anion, a 1,10-phenanthroline (phen) ligand and two benzoate anions. The crystal packing is stabilized by O—H⋯O hydrogen bonds and by π–π stacking between neighboring phen ligands, with a centroid–centroid distance of 3.557 (3) Å