Toxic Clumps in Huntington’s Disease May Protect the Brain Too

Huntington’s disease is tragically predictable. An inherited genetic mutation causes neurons to make distorted, sticky proteins. These proteins clump together and gradually overwhelm brain cells. The brain loses its ability to learn, remember, and make decisions.

This story is dogma in neuroscience. But decades of research and drugs targeting the clumps have had little success. Scientists are now wondering: Is there more to the story? In a twist, a team from the Hebrew University of Jerusalem and collaborators found that protein clumps may 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 just one part. Inclusion bodies also changed the activity of genes involved in neuroinflammation—even in 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 only for a cell model of Huntington’s disease in a petri dish. And inclusion bodies could be a double-edged sword: protective in the beginning and detrimental later on. Still, acknowledging them as a more complicated villain could better inform strategies for disorders that take over our minds like Huntington’s.

"Our results reveal…that these structures are not merely byproducts of disease, but a central factor in the cell's ability to mount a protective response against stress,” said study author Eran Meshorer in a press release.

The Problem With PolyQ

It’s long been believed that protein clumps in the brain gradually erode cognition. Whether they’re the main driver of neurodegenerative disorders is still debated, but their presence accelerates brain cell injury, causing neurons to wither away.

Alzheimer’s disease, for example, is associated with two sets of protein clumps. One lives inside neurons (tau) and another gunks up the space between cells (amyloid). Decades of research aimed at 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 control movement, emotion, and even the perception of time. Lou Gehrig's disease, or ALS, produces inclusion bodies inside motor neurons, leading to 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 build highways that transport all sorts of biological cargo, from molecules to organelles. The protein also plays an essential role during early brain development and neural wiring in adulthood.

But a mutant form of the HTT gene can wreak havoc. A common 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 thought to be detrimental. Some act like sticky tape that captures healthy proteins, such as those involved in gene expression, and torpedoes cellular health.

But telltale signs in cultured rat brain cells suggest a more nuanced story: Inclusion bodies could also be protective, sequestering mutant proteins as an early form of protection.