Huntington’s disease is tragically predictable. An inherited genetic mutation causes neurons to make distorted, sticky proteins. These proteins clump together and regularly overwhelm brain cells. The brain loses its ability to learn, remember, and make decisions.
This story is dogma in neuroscience. But a long time of research and medicines targeting the clumps have had little success. Scientists are actually wondering: Is there more to the story? In a twist, a team from the Hebrew University of Jerusalem and collaborators found that protein clumps could also be a neuron’s first line of defense against damage.
The misfolded or malfunctioning proteins are quarantined inside bubbly hubs called “inclusion bodies.” Often considered detrimental to cell health, disrupting their formation unexpectedly led to cells becoming more sensitive to stressors often seen in neurodegenerative diseases.
Physical separation played only one part. Inclusion bodies also modified the activity of genes involved in neuroinflammation—even within the absence of immune cells. Scouting the genetic landscape of cells derived from patients with severe Huntington’s disease, the team homed in on a “master regulator” gene, ATF3, that orchestrates immune responses. Removing the gene lessened inclusion bodies’ protective effects against damage in cultured cells.
To be clear, the findings are just for a cell model of Huntington’s disease in a petri dish. And inclusion bodies might be a double-edged sword: protective at first and detrimental afterward. Still, acknowledging them as a more complicated villain could higher inform strategies for disorders that take over our minds like Huntington’s.
“Our results reveal…that these structures usually are not merely byproducts of disease, but a central consider the cell’s ability to mount a protective response against stress,” said study writer Eran Meshorer in a press release.
The Problem With PolyQ
It’s long been believed that protein clumps within the brain regularly erode cognition. Whether or not they’re the most important driver of neurodegenerative disorders remains to be debated, but their presence accelerates brain cell injury, causing neurons to wither away.
Alzheimer’s disease, for instance, is related to two sets of protein clumps. One lives inside neurons (tau) and one other gunks up the space between cells (amyloid). Many years of research geared toward removing amyloid clumps have met with minimal success, earning these doomed efforts the notorious nickname “graveyard of dreams.” Despite their struggles, the FDA recently approved two major drugs that remove amyloid clumps and modestly slow cognitive decline, though the approval has been controversial due to doubts about safety.
Other untreatable neurodegenerative disorders also fall into this category. Clumps formed in Parkinson’s disease erode the brain’s ability to manage movement, emotion, and even the perception of time. Lou Gehrig’s disease, or ALS, produces inclusion bodies inside motor neurons, resulting in muscle weakness and trouble swallowing. The disease eventually robs people of speech and motion.
These diseases often have multiple genetic and environmental triggers. Huntington’s, in contrast, is entirely genetic. The condition stems from the genome over-copying parts of the huntingtin gene (HTT), which normally makes a key protein also called huntingtin.
Normally, cells use the protein’s large, stackable structure to construct highways that transport all kinds of biological cargo, from molecules to organelles. The protein also plays a vital role during early brain development and neural wiring in maturity.
But a mutant type of the HTT gene can wreak havoc. A typical mutation, called polyQ expansion, produces unwieldy, misfolded proteins. Nearly 30 years ago, researchers found that these errant proteins aggregate inside parts of the cell. The clumps, or inclusion bodies, were widely considered detrimental. Some act like sticky tape that captures healthy proteins, comparable to those involved in gene expression, and torpedoes cellular health.
But telltale signs in cultured rat brain cells suggest a more nuanced story: Inclusion bodies may be protective, sequestering mutant proteins as an early type of protection.
A Tale of Two
The common consider diseases featuring polyQ mutation is repetition. Mutated genes have long, duplicated sequences of the DNA letters cytosine, adenosine, and guanine (CAG). More CAG repeats within the genome translates into earlier disease onset.
All of us have this DNA triplet in our HTT gene. But greater than 39 repeats leads to longer, toxic huntingtin proteins. Severe cases of Huntington’s can feature over 100 CAG repeats, transforming the often free-floating protein employees into sticky, dysfunctional layabouts.
In the brand new study, the researchers first established a baseline. They used the gene editing tool CRISPR-Cas9 to cut back CAG repeats in cells derived from Huntington’s patients—which carried over 180 copies—to close normal levels.
They then tagged the cells with a fluorescent marker that causes huntingtin proteins to glow shiny green under the microscope. This let the team track protein aggregation in real time. Though they shared the identical genetics, some cells formed inclusion bodies; others didn’t.
The team next challenged them with a chemical known to cause cellular stress. People who formed clumps survived way more frequently than those who didn’t. It was a “striking difference,” the authors wrote. “Once a mutant PolyQ protein is expressed, the formation of IBs [inclusion bodies] protect[s] the cells moderately than inflict[s] harm, a minimum of short-term.”
Inflammation appears to be key. Although grown side-by-side, a genetic screen revealed cells with inclusion bodies were especially abundant in a gene called ATF3, which is thought to manage inflammation. Eliminating the gene worn out the neurons’ ability to form inclusion bodies, making them more vulnerable.
“Our results reveal a previously unknown role for ATF3 in orchestrating the formation of inclusion bodies in human neurons,” said Meshorer.
These are very early results. An immune molecule bridges ATF3 and inflammation and is related to Huntington’s disease. Its levels are higher in patients with the condition. Increasing ATF3 activity could amp up the variety of protective inclusion bodies and provides neurons a fighting probability.
The findings suggest inclusion bodies gather free-floating mutant proteins into clumps to guard neurons and reduce brain damage—a minimum of firstly of the disease. Nonetheless, lab experiments rarely translate to treatments. How briskly inclusion bodies form and once they begin to emphasize cells stays to be seen. Meanwhile, a gene therapy for Huntington’s is underway, and promising leads to a small trial suggest another path for treatment.
Still, the study challenges the concept protein clumps are at all times detrimental. If replicated in other neurodegenerative diseases comparable to Alzheimer’s or ALS and if we will find out how long protection lasts, the outcomes could pave the best way for better-timed treatment that works with the body’s protection, not against it.