AI Article Synopsis
- The abnormal GGGGCC hexanucleotide repeat expansions in the C9orf72 gene are linked to severe neurodegenerative diseases like ALS and frontotemporal dementia.
- The toxic RNA forms foci that trap RNA binding proteins, disrupting RNA processing and contributing to neurodegeneration.
- The study details the crystal structure of a specific RNA G-quadruplex, providing insight into its role in neurological toxicity and offering a basis for future therapeutic developments.
Article Abstract
The abnormal GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause the fatal neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal dementia. The transcribed RNA HREs, short for r(G4C2)n, can form toxic RNA foci which sequestrate RNA binding proteins and impair RNA processing, ultimately leading to neurodegeneration. Here, we determined the crystal structure of r(G4C2)2, which folds into a parallel tetrameric G-quadruplex composed of two four-layer dimeric G-quadruplex via 5'-to-5' stacking in coordination with a K+ ion. Notably, the two C bases locate at 3'- end stack on the outer G-tetrad with the assistance of two additional K+ ions. The high-resolution structure reported here lays a foundation in understanding the mechanism of neurological toxicity of RNA HREs. Furthermore, the atomic details provide a structural basis for the development of potential therapeutic agents against the fatal neurodegenerative diseases ALS/FTD.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11260476 | PMC |
| http://dx.doi.org/10.1093/nar/gkae473 | DOI Listing |
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