Journal News

Do ribosomal traffic jams cause Huntington’s disease?

Uzma Rentia
By Uzma Rentia
Sept. 5, 2024

Huntington's disease, or HD, a genetic disorder that affects about one in every 10,000 people in the U.S., is inherited in an autosomally dominant manner, meaning that a person with the condition has a 50% chance of passing it on to their child. HD kills important neurons in the brain, causing uncontrollable movements and cognitive and psychiatric changes.

While scientists have long known that HD is caused by a cytosine–adenine–guanine trinucleotide repeat in the Huntingtin gene contained on chromosome 4, they are still studying the biological mechanisms that guide the disease process. In particular, researchers have implicated mitochondrial dysfunction in the pathophysiology of HD, and it is an ongoing focus of study.

Investigators at the Wertheim University of Florida Scripps Research Institute recently used novel techniques to examine mRNA translation within the mitochondria of mice genetically altered to have HD. They found that ribosomes — particles responsible for creating proteins from instructions encoded in mRNA — get clustered and jammed on mitochondrial mRNA transcripts. The team published these new findings, in the journal Molecular & Cellular Proteomics.

Srinivasa Subramaniam, an associate professor at Wertheim UF Scripps, was the lead author on the study. “Imagine going from Baltimore to Washington, D.C., and there are too many cars, and they are all jammed up,” he said. “Just because there are many cars does not mean they are all reaching their destination.

“So, what does that mean for the patient? That means that the patient may have difficulty translating their mitochondrial protein. And that may lead to problems in the assembly of these complexes, which may lead to problems in mitochondrial function.”

Mitochondrial protein synthesis is diminished in Huntington’s disease cells. These mouse striatal cells have a normal genotype (left) or are heterozygous (center) or homozygous (right) for a Huntington’s disease mutation. Puromycin uptake is shown in green and represents the cellular protein translation rate. Nuclei are shown in blue.
MCP
Mitochondrial protein synthesis is diminished in Huntington’s disease cells. These mouse striatal cells have a normal genotype (left) or are heterozygous (center) or homozygous (right) for a Huntington’s disease mutation. Puromycin uptake is shown in green and represents the cellular protein translation rate. Nuclei are shown in blue.

This project followed from Subramaniam’s previous work, which demonstrated high expression of fragile X messenger ribonucleoprotein, or FMRP, a protein that blocks ribosomes in HD. Consequently, he was curious to see the spatial distribution of ribosomes on mitochondrial mRNA, so Subramaniam turned to a technique called Ribo-Seq, which provides a snapshot of the location and density of ribosomes on a given mRNA transcript. He had no experience with the technique and immediately faced challenges.

“I am a biochemist by training,” Subramaniam said. “So I needed to sit and write hundreds of emails like ‘Can you help me?’ all over the world.”

He connected with collaborators in France and Ireland and took on a postdoc with Ribo-Seq experience. Almost four years later, Subramaniam and his lab published the results of their work. And with these results come new questions.

Previous research has shown that deleting the FMRP protein can prevent some cognitive deficits observed in HD. Subramaniam wants to investigate how modulating the expression of FMRP can affect the spatial distribution of ribosomes on mRNA transcripts. He also wants to see how communication between the cytoplasm and mitochondria contributes to what he likens to a "traffic jam."   He hypothesizes that the cytoplasm inhibits proper functioning of mitochondrial mRNA, creating confusion.

“Imagine if you are traveling through a tunnel, and you close that tunnel,” he said. “Who puts on that brake? Who triggered that pathway? What is the signal that makes this traffic jam? That is what I want to know in more detail at the molecular level.”

He hopes this work has practical applications as well.

“How can we use small-molecule screening to reverse this phenotype?” he said. “My goal is to identify the mechanisms and then leverage potential therapeutics.”

Enjoy reading ASBMB Today?

Become a member to receive the print edition four times a year and the digital edition monthly.

Learn more
Uzma Rentia
Uzma Rentia

Uzma Rentia is a third-year medical student at George Washington University in Washington, D.C., who is also enrolled in the University of California, San Diego Science Writing Certificate Program. She is an ASBMB Today volunteer contributor.

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Antibiotic sensor directly binds drug in resistant bacteria
Journal News

Antibiotic sensor directly binds drug in resistant bacteria

Oct. 8, 2025

Researchers at Drexel University uncover how the vancomycin-resistant bacterial sensor binds to the antibiotic, offering insights to guide inhibitor design that restores antibiotic effectiveness against hospital-acquired infections.

ApoA1 reduce atherosclerotic plaques via cell death pathway
Journal News

ApoA1 reduce atherosclerotic plaques via cell death pathway

Oct. 1, 2025

Researchers show that ApoA1, a key HDL protein, helps reduce plaque and necrotic core formation in atherosclerosis by modulating Bim-driven macrophage death. The findings reveal new insights into how ApoA1 protects against heart disease.

Omega-3 lowers inflammation, blood pressure in obese adults
Journal News

Omega-3 lowers inflammation, blood pressure in obese adults

Oct. 1, 2025

A randomized study shows omega-3 supplements reduce proinflammatory chemokines and lower blood pressure in obese adults, furthering the understanding of how to modulate cardiovascular disease risk.

AI unlocks the hidden grammar of gene regulation
Feature

AI unlocks the hidden grammar of gene regulation

Sept. 30, 2025

Using fruit flies and artificial intelligence, Julia Zeitlinger’s lab is decoding genome patterns — revealing how transcription factors and nucleosomes control gene expression, pushing biology toward faster, more precise discoveries.

Zebrafish model links low omega-3s to eye abnormalities
Journal News

Zebrafish model links low omega-3s to eye abnormalities

Sept. 24, 2025

Researchers at the University of Colorado Anschutz developed a zebrafish model to show that low maternal docosahexaenoic acid can disrupt embryo eye development and immune gene expression, offering a tool to study nutrition in neurodevelopment.

Top reviewers at ASBMB journals
Observance

Top reviewers at ASBMB journals

Sept. 19, 2025

Editors recognize the heavy-lifters and rising stars during Peer Review Week.