New research reveals a surprising mechanism by which an inherited genetic mutation causes Huntington's disease, transforming the understanding of the fatal neurodegenerative disorder and suggesting potential avenues for prevention or delay.
A groundbreaking study has shed new light on the mechanisms behind Huntington's disease, revealing a surprising and intricate process by which an inherited genetic mutation leads to the death of brain cells . For decades, researchers have known that Huntington's is caused by a mutation in the Huntingtin (HTT) gene, but the precise way this mutation caused cell death remained a mystery.
This new research, conducted by scientists at the Broad Institute of MIT and Harvard, Harvard Medical School, and McLean Hospital, has uncovered a previously unknown mechanism.The study demonstrates that the inherited mutation itself is not inherently harmful to cells. Instead, it remains relatively innocuous for many years, gradually transforming into a highly toxic form over time. This transformation process, known as somatic expansion, involves the gradual lengthening of a specific DNA sequence within the HTT gene, composed of the three-letter code 'CAG.' In individuals with Huntington's, this CAG sequence is repeated at least 40 times, compared to the 15-35 repeats seen in healthy individuals. The researchers discovered that these DNA tracts with 40 or more CAG repeats can grow until they reach hundreds of repeats in length. However, this expansion occurs only within specific types of brain cells that are ultimately affected by Huntington's disease. Crucially, it is only when a cell's DNA expansion reaches a certain threshold number of CAGs – roughly 150 – that the cell becomes sick and eventually dies. The cumulative death of numerous such cells contributes to the development of the characteristic symptoms of Huntington's disease. This finding offers a potential explanation for the challenges faced by candidate Huntington's drugs that aim to reduce the expression of the HTT protein. Since very few cells possess the toxic version of the protein at any given time, these treatments may not be effective in a majority of cells. The study suggests that targeting the somatic expansion process itself, perhaps by preventing the lengthening of the CAG repeats, could delay or even prevent the onset of Huntington's disease in a significantly larger number of individuals. 'These experiments have fundamentally changed our understanding of how Huntington's develops,' said Steve McCarroll, a geneticist and neuroscientist and co-senior author of the study. 'This represents a novel way of conceptualizing how a mutation can lead to a disease, and we believe it will have broader implications for DNA-repeat disorders beyond Huntington's disease.
Huntington's Disease Genetic Mutation Somatic Expansion Brain Cells Neurodegenerative Disorder
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