Huntingtin through a multiomic lens
Tracing the effects of a single gene’s mutation can be hard. Huntington’s disease, for example, is caused by just one mutation — but that change reverberates throughout the brain. Research published in the journal Molecular & Cellular Proteomics shows that the mutant protein that causes Huntington’s can alter the binding properties of another protein, perhaps accounting for some of the mutation’s far-flung cellular effects.
Huntington’s disease, an as-yet-untreatable neurodegenerative disorder, is caused by a mutation that affects the protein huntingtin. Huntingtin is large to begin with; in patients, a repeat region in the gene adds an expanding tract of glutamine residues to the protein, making it sticky and prone to aggregate. But how the protein change leads to profound problems in neurons is up for debate.
“Very few proteins act as a monolithic structure,” said Joel Federspiel, a postdoctoral fellow in Ileana Cristea’s lab at Princeton University. Instead, most act in coordination with other proteins. The same is probably true for huntingtin — but previous interactomics studies turned up thousands of binding partners. Which ones are important for the way the disease develops?
Recent research had shown that reducing neuronal levels of the protein HDAC4, which binds to mutated huntingtin, may reduce Huntington’s symptoms, at least in mice. Oddly, however, blocking the enzymatic activity of HDAC4, which belongs to a class of enzymes that alter histone proteins that organize DNA, did not have the same effect.
To Federspiel and Cristea, the data suggested that HDAC4 was contributing to the onset of disease through a binding interaction either with huntingtin or with other proteins. So they hopped one ripple ring away from huntingtin protein itself to study how HDAC4 changes in a brain affected by the disease.
The researchers used immunoaffinity purification followed by mass spectrometry to catalogue all of the proteins that interact with HDAC4 in the mouse brain. In a mouse model of Huntington’s, they found major changes to the HDAC4 interactome around the age at which symptoms start to appear.
“You can, in a case like this, have hundreds to thousands of proteins or transcripts that are differentially regulated,” Federspiel said. “Trying to home in on just a few of those to focus on can be challenging. However, if you have more lines of evidence, then you start to see what things are common.”
To find the significant proteins, they layered in additional data from earlier transcriptome and proteome studies. After they applied what they called a lens of multiomics, a few insights came into focus.
In the mice with huntingtin mutations that were old enough to exhibit symptoms, HDAC4 associated with many huntingtin-binding proteins — more so than in the brains of healthy mice or younger mutants.
Many of the interacting proteins were involved in the organization of synapses and vesicle transport. In the mutant mice, those proteins interact with HDAC4 much more strongly. The effect was most noticeable in cells in the striatum, a brain region that controls movement and is affected greatly in Huntington’s disease.
That’s good circumstantial evidence that, in Huntington’s-affected brains, a changing HDAC4 interactome may contribute to symptoms. Exactly how, the researchers say, remains to be determined.
Enjoy reading ASBMB Today?
Become a member to receive the print edition four times a year and the digital edition monthly.
Learn moreGet 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

Melissa Moore to speak at ASBMB 2025
Richard Silverman and Melissa Moore are the featured speakers at the ASBMB annual meeting to be held April 12-15 in Chicago.

A new kind of stem cell is revolutionizing regenerative medicine
Induced pluripotent stem cells are paving the way for personalized treatments to diabetes, vision loss and more. However, scientists still face hurdles such as strict regulations, scalability, cell longevity and immune rejection.

Engineering the future with synthetic biology
Learn about the ASBMB 2025 symposium on synthetic biology, featuring applications to better human and environmental health.

Scientists find bacterial ‘Achilles’ heel’ to combat antibiotic resistance
Alejandro Vila, an ASBMB Breakthroughs speaker, discussed his work on metallo-β-lactamase enzymes and their dependence on zinc.

Host vs. pathogen and the molecular arms race
Learn about the ASBMB 2025 symposium on host–pathogen interactions, to be held Sunday, April 13 at 1:50 p.m.

Richard Silverman to speak at ASBMB 2025
Richard Silverman and Melissa Moore are the featured speakers at the ASBMB annual meeting to be held April 12-15 in Chicago.