| First Author | Bush JA | Year | 2022 |
| Journal | Proc Natl Acad Sci U S A | Volume | 119 |
| Issue | 48 | Pages | e2210532119 |
| PubMed ID | 36409902 | Mgi Jnum | J:351846 |
| Mgi Id | MGI:7437408 | Doi | 10.1073/pnas.2210532119 |
| Citation | Bush JA, et al. (2022) A blood-brain penetrant RNA-targeted small molecule triggers elimination of r(G(4)C(2))(exp) in c9ALS/FTD via the nuclear RNA exosome. Proc Natl Acad Sci U S A 119(48):e2210532119 |
| abstractText | A hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from the expansion, r(G(4)C(2))(exp), causes various pathologies, including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci. Here, we describe a small molecule that potently and selectively interacts with r(G(4)C(2))(exp) and mitigates disease pathologies in spinal neurons differentiated from c9ALS patient-derived induced pluripotent stem cells (iPSCs) and in two c9ALS/FTD mouse models. These studies reveal a mode of action whereby a small molecule diminishes intron retention caused by the r(G(4)C(2))(exp) and allows the liberated intron to be eliminated by the nuclear RNA exosome, a multi-subunit degradation complex. Our findings highlight the complexity of mechanisms available to RNA-binding small molecules to alleviate disease pathologies and establishes a pipeline for the design of brain penetrant small molecules targeting RNA with novel modes of action in vivo. |
