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G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments

2014; National Academy of Sciences; Volume: 111; Issue: 51 Linguagem: Inglês

10.1073/pnas.1407361111

1091-6490

Pavel Ivanov, Elizabeth O’Day, Mohamed M. Emara, Gerhard Wagner, Judy Lieberman, Paul Anderson,

RNA Research and Splicing

Significance Angiogenin is a stress-activated ribonuclease that cleaves tRNA to produce bioactive small noncoding RNAs [tRNA-derived, stress-induced RNAs (tiRNAs)] that function in a cytoprotective stress response program. Point mutations that reduce its ribonuclease activity are found in a subset of patients with ALS, a fatal neurodegenerative disease. We have found that selected tiRNAs assume G-quadruplex (G4) structures that are necessary for cytoprotective and prosurvival functions. Moreover, stable DNA analogs of these G4-containing tiRNAs spontaneously enter motor neurons and confer cytoprotection against stress. Our results identify tiRNAs as leading compounds for the development of a new class of neuroprotective drugs and give insights into the molecular mechanisms underlying the pathobiology of expanded G4-forming hexanucleotide repeats in the C9ORF72 gene.