Huntington’s disease (HD) is a progressive brain disorder caused by a mutated gene. This disease causes changes in the central area of the brain, which affects movement, mood, and cognition. Scientists discovered that the mutated gene, HTT, caused Huntington’s disease twenty-eight years ago. Yet, there is still no cure.
In a new study, “Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease,” published in Nature Communications, researchers from Scripps Research demonstrated that the mutated huntingtin protein slows brain cells’ ribosomes.
“The polyglutamine expansion of huntingtin (mHTT) causes HD and neurodegeneration, but the mechanisms remain unclear,” wrote the researchers. “Here, we found that mHtt promotes ribosome stalling and suppresses protein synthesis in mouse HD striatal neuronal cells.”
“The ribosome has to keep moving along to build the proteins, but in Huntington’s disease, the ribosome is slowed,” explained Srinivasa Subramaniam, PhD, a neuroscientist at Scripps and author of the study. “The difference may be two-, three-, four-fold slower. That makes all the difference.”
The main function of ribosomes is to produce proteins that are used both inside the cell and sent outside the cell. Without ribosomes, the human body would not be able to produce the proteins it needs to survive and metabolism would come to a screeching halt.
“It’s not possible for the cell to stay alive without protein production,” Subramaniam said.
Huntington’s disease is caused by an excessive number of genetic repeats of three DNA building blocks—cytosine (C), adenine(A), and guanine (G), 40 or more of these repeats in the HTT gene causes the disease. The symptoms are caused by degeneration of brain tissue that begins in a region called the striatum, and then spreads. The striatum is the region deep in the center of the brain that controls voluntary movement and responds to social reward.
The researchers used striatal cells engineered to have three different degrees of CAG repeats in the HTT gene. They assessed the impact of the CAG repeats using a technology called Ribo-Seq, and mRNA-seq, which allowed them to see a snapshot of which genes were active and which were not.
The researchers observed that in Huntington’s cells, proteins were slowed. When they blocked the cells’ ability to make mutant huntingtin protein, they observed increased speed of ribosome movement and protein synthesis.
The mutant huntingtin protein was seen bounding directly to the ribosomal proteins and the ribosomal assembly. This not only affected the speed of protein synthesis, but it affected the ribosomal density within the cell.
“The idea that the ribosome can stall before a CAG repeat is something people have predicted. We can show that it’s there,” Subramaniam stated. “There’s a lot of additional work that needs to be done to figure out how the CAG repeat stalls the ribosome, and then perhaps we can make medications to counteract it.”
Their findings pave a new way for the development of therapeutics, and may provide insights for other neurodegenerative diseases in which ribosome stalling plays a role.
