Paul Anderson

A team of researchers led by Paul Anderson, MD, PhD, of the Division of Rheumatology, Immunology and Allergy, has found that tiRNAs – small, non-coding RNA fragments – may help assemble structures that promote the survival of motor neurons. Mutations in angiogenin, the ribonuclease that cleaves tRNA to produce tiRNAs, are found in a subset of patients with the neurodegenerative disease ALS. The team reports these results in Proceedings of the National Academy of Sciences.

The researchers had previously shown that angiogen (ANG), a stress-activated ribonuclease, splits tRNAs to produce fragments (known as tRNA-derived, stress-induced RNAs or tiRNAs) that cooperate with other molecules to induce the assembly of stress granules (SGs).  In their latest paper, the researchers show that specific tiRNAs can assemble a G-quadruplex (G4) structure, a four-stranded nucleic acid sequence rich in guanine. DNA analogues of these bioactive fragments (tiDNAs) spontaneously enter into motor neurons and trigger a neuroprotective response.

Point mutations that reduce angiogenin’s activity are found in a subset of patients with ALS, a fatal disease that affects motor neurons. In addition, the most common genetic cause of ALS – a stretch of GGGGCC repeats found in the gene C9ORF72 – interferes with the ability of tiRNAs to produce SGs. The new findings suggest that angiogenin and tiRNAs are components of a neuroprotective pathway that may contribute to the pathogenesis of ALS.

“Our results identify tiDNAs as lead compounds for the development of a new class of neuroprotective drugs and give insights into the molecular mechanisms underlying the pathobiology of [the most common genetic cause of ALS],” the authors write.