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Alzheimer's Disease

Novel Mechanism behind Neurodegeneration Discovered

In a study appearing in Science researchers from the Jackson Laboratory say that neurodegeneration in mice is caused by a defect in transfer RNA (tRNA). A stalling or pausing of the protein production process in the neuronal ribosomes is triggered by a mutation in a gene that produces tRNAs operating only in the central nervous system. Neurodegeneration occurs when another protein GTPBP2, is also missing.

Neurodegeneration is at the root of diseases like Alzheimer’s, Parkinson’s, Huntington’s and Lou Gehrig’s, or amyotrophic lateral sclerosis. Even as scientists dwell deeper into the causes of neurodegeneration, there is a great deal of evidence suggesting that neurons are much more sensitive than other types of cells to disruptions in how proteins are made and how they fold.

tRNAs play a critical role in translating 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.”

In their study Dr. Ackerman and her colleagues at the Jackson Lab, The Scripps Research Institute in La Jolla, CA, and Kumamoto University in Japan say that a mutation in the tRNA gene n-Tr20 as the genetic reason for 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.

“We [discovered] that loss of GTPBP2 in mice with a mutation in a tRNA gene that is expressed only 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.

A partner protein called GTPBP2 can largely overcome this stalling. But when this partner is missing the stalling intensifies. This is thought to be a driving force behind the neurodegeneration seen in these mice.

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