Huntington’s disease is mediated by slow-moving protein building machines in cells

JUPITER, FL – In 1993, scientists discovered that one mutated gene, HTT, caused Huntington’s disease, raising high hopes for rapid healing. But today, treatment is not yet allowed.

One problem is getting a little understanding of how the huntant mutant protein causes brain cell death, says neuroscientist Srinivasa Subramaniam, PhD, of Scripps Research, Florida. In a new study published in Nature Communication on Friday, the Subramaniam group has shown that the mutated huntin protein slows down brain cell protein building machinery, called ribosomes.

“The ribosome has to keep moving to pick up the proteins, but in Huntington’s disease, the ribosome is made slower,” Subramaniam says. “The difference may be two, three, four- slower folding. That makes a big difference. ”

In cells there are millions of ribosomes each, all of which move forward and use genetic information to accumulate amino acids and make proteins. Damage of their activity is ultimately destructive to the cell, Subramaniam says.

“The cell cannot survive without protein production,” he says.

The team’s discovery was made possible by recent advances in gene translational tracking technologies, Subramaniam says. The results suggest a new pathway for pharmacological development, and have implications for a number of neurodegenerative diseases in which ribosome installation appears to be involved.

Huntington’s disease affects about 10 people per 100,000 in the United States. It is caused by excessive genetic transplants of three DNA building blocks. Known by the letters CAG, short for cytosine, adenine and guanine, 40 or more of these repeats in the HTT gene cause degenerative brain disease, which is ultimately fatal. The more relapses present, the sooner symptoms occur, which include behavioral disturbances, difficulty moving and balancing, weakness and difficulty speaking and eating. The symptoms are caused by the degeneration of brain bones that begin in an area called the striatum, and then spread. The striatum is the deep region in the center of the brain that controls voluntary movement and responds to social reward.

For their experiments, the scientists used striatal cells that were engineered to produce three different levels of CAG replication in the HTT gene. They evaluated the effect of CAG repeats using a technology called Ribo-Seq, short for high-resolution global ribosome footprint profile, as well as mRNA-seq, a method that allows to obtain a picture of the genes active, and not in a particular way. cell at a given time.

The scientists in Huntington’s cells found that the translation of many, not all, was reduced. To validate the detection, they inhibited the ability of the cells to produce mutant protein, and found the speed of ribosome movement and protein synthesis. They also evaluated how huntin mutant proteins affected the translation of other genes, and ruled out that another ribosome binding protein, Fmrp, could cause the slow effect.

Further experiments provided little insight into how the mutant huntin protein affected the function of the ribosomes. They found that it was directly related to ribosomal proteins and the ribosomal synthesis, and not only affected the speed of protein synthesis, but also the ribosomal density within the cell.

There are still many issues, Subramaniam says, but the progress offers new guidelines for helping people with Huntington’s disease.

“The idea that the ribosome can stop before CAG is repeated is something that humans have predicted. We can show that it exists,” Subramaniam says. “There’s a lot of extra work that needs to be done to figure out how the CAG repetition stops the ribosome, and then maybe we can do medications to counteract it.”

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In addition to Subramanium, the authors of the paper, “Mutant Huntingtin Stalls Ribosomes and Represses Protein Synthesis in a Cellular Model of Huntington Disease,” include Mehdi Eshraghi, Pabalu Karunadharma, Neelam Shahani, Nicole Galli, Manish Sharma, Uri Nimrod Ramírez-Jarquín, Katie Florescu, and Jennifer Hernandez from Scripps Research; Juliana Blin and Emiliano P Ricci of RNA Metabolism in Immunology and Disease Laboratory, Lyon Laboratory of Biology and Cellular Modeling Lyon, France; Audrey Michel of RiboMaps of Cork, Ireland; and Nicolai Urban of the Max Planck Institute of Neuroscience in Jupiter, Florida.