Researchers from the Jackson Laboratory say they have pinpointed a mechanism behind neurodegeneration in mice, one that involves a defect in transfer RNA (tRNA). Their study (“Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration”) in Science reports that a mutation in a gene that produces tRNAs operating only in the central nervous system results in a stalling or pausing of the protein production process in the neuronal ribosomes. When another protein the researchers identified, GTPBP2, is also missing, neurodegeneration results.

“Our study demonstrates that individual tRNA genes can be tissue-specifically expressed in vertebrates,” said Susan Ackerman, Ph.D., from the Jackson Lab and a Howard Hughes Investigator. “Mutations in such genes may cause disease or modify other phenotypes. This is a new area to look for disease mechanisms.”

Neurodegeneration is poorly understood, yet it underlies major human diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and ALS (amyotrophic lateral sclerosis, also known as Lou Gehrig's disease). While the causes of neurodegeneration are still coming to light, there is mounting evidence that neurons are exquisitely sensitive—much more so than other types of cells—to disruptions in how proteins are made and how they fold.

tRNAs are critical in translating the genetic code into proteins. “Multiple genes encode almost all tRNA types,” explained Dr. Ackerman. “In fact, AGA codons are decoded by five tRNAs in mice. Until now, this apparent redundancy has caused us to completely overlook the disease-causing potential of mutations in tRNAs, as well as other repetitive genes.”

Dr. Ackerman and her colleagues at the Jackson Lab, The Scripps Research Institute in La Jolla, CA, and Kumamoto University in Japan pinpointed a mutation in the tRNA gene n-Tr20 as a genetic culprit behind the neurodegeneration observed in mice lacking GTPBP2. Remarkably, the tRNA's activity is confined to the brain and other parts of the central nervous system, in both mice and humans. The tRNA encoded by n-Tr20 recognizes the triplet code, AGA (which specifies the amino acid arginine).

“We [discovered] that loss of GTPBP2, a novel binding partner of the ribosome recycling protein Pelota, in mice with a mutation in a tRNA gene that is specifically expressed in the central nervous system causes ribosome stalling and widespread neurodegeneration,” the investigators wrote. “Our results not only define GTPBP2 as a ribosome rescue factor but also unmask the disease potential of mutations in nuclear-encoded tRNA genes.”

The n-Tr20 defect disrupts how proteins are made. Specifically, it causes the ribosomes to stall when they encounter an AGA triplet.

Such stalling can be largely overcome, thanks to the work of a partner protein called GTPBP2. But when this partner is missing—as it is in the mutant mice that Dr. Ackerman and her colleagues studied—the stalling intensifies. This is thought to be a driving force behind the neurodegeneration seen in these mice.

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