<\/p>\n
Huntington\u2019s 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.<\/p>\n
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<\/a> that protein clumps could also be a neuron\u2019s first line of defense against damage.<\/p>\n The misfolded or malfunctioning proteins are quarantined inside bubbly hubs called \u201cinclusion bodies.\u201d Often considered detrimental to cell health, disrupting their formation unexpectedly led to cells becoming more sensitive to stressors often seen in neurodegenerative diseases.<\/p>\n Physical separation played only one part. Inclusion bodies also modified the activity of genes involved in neuroinflammation\u2014even within the absence of immune cells. Scouting the genetic landscape of cells derived from patients with severe Huntington\u2019s disease, the team homed in on a \u201cmaster regulator\u201d gene, ATF3, that orchestrates immune responses. Removing the gene lessened inclusion bodies\u2019 protective effects against damage in cultured cells.<\/p>\n To be clear, the findings are just for a cell model of Huntington\u2019s 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\u2019s.<\/p>\n “Our results reveal\u2026that these structures usually are not merely byproducts of disease, but a central consider the cell’s ability to mount a protective response against stress,\u201d said study writer Eran Meshorer in a press release<\/a>.<\/p>\n It\u2019s long been believed that protein clumps within the brain regularly erode cognition. Whether or not they\u2019re the most important driver of neurodegenerative disorders remains to be debated, but their presence accelerates brain cell injury, causing neurons to wither away.<\/p>\n Alzheimer\u2019s 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 \u201cgraveyard of dreams.\u201d 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<\/a> due to doubts about safety.<\/a><\/p>\n Other untreatable neurodegenerative disorders also fall into this category. Clumps formed in Parkinson\u2019s disease erode the brain\u2019s ability to manage movement, emotion, and even the perception of time<\/a>. 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.<\/p>\n These diseases often have multiple genetic and environmental triggers. Huntington\u2019s, in contrast, is entirely genetic. The condition stems from the genome over-copying parts of the huntingtin gene (HTT<\/em>), which normally makes a key protein also called huntingtin.<\/p>\n Normally, cells use the protein\u2019s 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.<\/p>\n But a mutant type of the HTT<\/em> gene can wreak havoc. A typical mutation, called polyQ expansion<\/a>, produces unwieldy, misfolded proteins. Nearly 30 years ago, researchers found that these errant proteins<\/a> aggregate inside parts of the cell. The clumps, or inclusion bodies, were widely considered detrimental. Some act like sticky tape that captures healthy proteins<\/a>, comparable to those involved in gene expression<\/a>, and torpedoes cellular health.<\/p>\n But telltale signs<\/a> in cultured rat brain cells suggest a more nuanced story: Inclusion bodies may be protective, sequestering mutant proteins as an early type of protection.<\/p>\n<\/div>\n 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.<\/p>\n All of us have this DNA triplet in our HTT<\/em> gene. But greater than 39<\/a> repeats leads to longer, toxic huntingtin proteins. Severe cases of Huntington\u2019s can feature over 100 CAG repeats, transforming the often free-floating protein employees into sticky, dysfunctional layabouts.<\/p>\nThe Problem With PolyQ<\/h2>\n
A Tale of Two<\/h2>\n