Nerve cell protein factory downtime

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Charcot-Marie-Tooth disease (CMT) is a rare hereditary disease. This occurs when genetic changes interfere with the transmission of nerve signals from the brain to the muscles of the extremities, especially the muscles of the lower extremities. This causes a gradual loss of muscle tissue in the lower extremities. Early symptoms of the disease, such as pain and difficulty walking, usually appear in childhood and adolescence. In Germany alone, an estimated 30,000 people live with CMT.

Enzyme changes

“It has long been known that mutations in a gene encoding an enzyme called aminoacyl-tRNA synthetase (aaRS) can cause CMT,” said the mechanism of non-coding RNA and cytoplasmic gene regulation laboratories at the Berlin Institute. The person in charge, Dr. Marina Chekulaeva, explains. Medical Systems Biology (BIMSB), which is part of the Berlin-based Max Delbrück Molecular Medicine Center of the Helmholtz Association (MDC).

These enzymes are required for the production of cellular proteins in the ribosome, the cellular protein factory. Their work involves aminoacylation, which binds an amino acid to another molecule, the so-called tRNA.This allows individuals amino acid They are linked together in the ribosome to form protein chains according to the genetic blueprint stored in DNA.

Translation is impaired by mutations

“The paradox is that these mutations do not interfere with aminoacylation activity, but interfere with translation, the production of proteins in the ribosome,” says Chekulaeva. “To understand this mechanism, my team and I scrutinized how mutations in the glycyl tRNA synthetase affect the translation process.” This enzyme is CMT type 2-D (CMT2D). It varies in patients with a common form of CMT disease known as.

In their study, researchers used ribosome profiling to evaluate ribosome activity in detail. “This technique helps us identify the exact codons where protein production stops, and quantify how often it occurs,” said the lead author of the study and a PhD student in Chekulaeva’s lab. Samantha Mendonsa explains.

Protein chain is too short

“We found that genetic alterations in CMT patients initially lacked glycyl tRNAs available for translation,” says Mendonsa. “This causes the ribosome to stop protein production at the site where the amino acid glycine is added to the growing protein chain.” protein Therefore, the chain will stop. “Pause of elongation at the glycine site also elicits an integrated stress response, leading to confusion in translation initiation,” she reports. As a result, protein production is reduced.

Mendonsa and Chekulaeva are convinced that their findings can provide a new way of treating CMT for which there is currently no causal cure. “One possibility is the administration of tRNAs to overcome neuronal deficiencies and thus reduce ribosome pauses,” says Chekulaeva. “Another approach may be to use relevant therapies to suppress the integrated stress response.” Still, it is now the job of clinical researchers to pursue these paths further. Say that.

Unresolved questions

“Our team is interested in, for example, the open question of how and why ribosome pauses impair the function of the motor and sensory nerve fibers that connect the brain to the lower extremities.” Chekulaeva says. The answer to that question can be very beneficial to people with CMT.

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For more information:
The Charcot-Marie-Tooth mutation in Samantha Mendonsa et al, a glycyl tRNA synthetase, stalls the ribosome in its preregulatory state and activates an integrated stress response. Nucleic acid research (2021). DOI: 10.1093 / nar / gkab730

Quote: Nerve cell protein factory downtime (September 15, 2021) is from September 2021 Obtained on the 15th.

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Nerve cell protein factory downtime

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