Huntington’s Disease May Be Driven by Slowed Protein-Building Machinery in Cells; New Study Shows That Mutant Huntingtin Protein Slows Ribosomes

In 1993, scientists discovered that a single mutated gene, HTT, caused Huntington's disease, raising high hopes for a quick cure. Yet today, there's still no approved treatment. One difficulty has been a limited understanding of how the mutant huntingtin protein sets off brain cell death, says neuroscientist Srinivasa Subramaniam, PhD, of Scripps Research, Florida. In a new study published online on March 5, 2021 in Nature Communications, Dr. Subramaniam's group has shown that the mutated huntingtin protein slows brain cells' protein-building machines, called ribosomes. "The ribosome has to keep moving along to build the proteins, but in Huntington's disease, the ribosome is slowed," Dr. Subramaniam says. "The difference may be two-, three-, four-fold slower. That makes all the difference." The open-access Nature Communications article is titled “"Mutant Huntingtin Stalls Ribosomes and Represses Protein Synthesis in a Cellular Model of Huntington Disease” ( Cells contain millions of ribosomes each, all whirring along and using genetic information to assemble amino acids and make proteins. Impairment of their activity is ultimately devastating for the cell, Dr. Subramaniam says. "It's not possible for the cell to stay alive without protein production," he says. The team's discoveries were made possible by recent advancements in gene translation tracking technologies, Dr. Subramaniam says. The results suggest a new route for development of therapeutics, and have implications for multiple neurodegenerative diseases in which ribosome stalling appears to play a role.
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