Biological engineers at Massachusetts Institute of Technology (MIT) in the US have discovered that the gene that causes Huntington’s disease, a fatal neurodegenerative disorder, damages brain cell function by disrupting the on-off switching patterns of other genes. They hope the discovery will lead to ways of restoring normal gene expression that can be used in treatments to slow or stop the progression of the disease in its early stages. Ernest Fraenkel, an associate professor of biological engineering at MIT, and colleagues, write about their findings in the Proceedings of the National Academy of Sciences. In a statement issued on 16 January, Fraenkel explains his group is very interested in the earliest phases of Huntington’s, “because that’s when there’s the most hope that you could either slow down or stop progression of the disease, and allow people to live healthy lives much longer.” “By the time there is much more severe neurodegeneration, it’s unlikely that you’re going to be able to reverse the damage,” he adds.

Gene for Huntington’s Disease Huntington’s disease is a fatal neurodegenerative disorder that affects about 30,000 Americans. It is a genetic disease that typically strikes in midlife and causes progressive death of specific areas of the brain. Most of the damage is to the basal ganglia, a part of the brain that is responsible for many functions, including voluntary control of muscles and habit formation. The gene for Huntington’s disease, which was discovered about 20 years ago, codes for a mutant protein called “huntingtin” that collects in cells. The mutant gene contains many extra repeats of DNA sequences, but until this study, how such extra length produces the symptoms of Huntington’s was a complete mystery.

Chemical Modification of DNA DNA carries the blueprint or instructions for making proteins that do the work of creating and controlling cells. A process called transcription uses a special group of proteins to “read” the instructions in the DNA. But a transcription protein can’t read a DNA instruction if the corresponding section of DNA is blocked. This is how genes can be “switched on and off”, forming an intricate pattern of gene expression that ensures the correct instruction is transcribed at the right time for a healthy organism to grow and live. One way of blocking access to genes is to attach methyl groups to the relevant sections of DNA. And there are genes that do this as ways to control when other genes are switched on and off. It was only recently that scientists realized that DNA methylation patterns aren’t fixed during embryonic development, but can change during an adult’s lifetime. In fact, they are coming round to the view that it is an active process involved in a wide range of normal cell behavior.

Study Finds Unexpected Patterns of DNA Methylation For their study, Fraenkel and colleagues measured changes in DNA methylation patterns in cells from the brains of mouse embryos with early stage Huntington’s disease. The cells were from the striatum, which is the largest part of the basal ganglia. The striatum is where planning of movement occurs and is severely affected by Huntington’s disease. The researchers were surprised to find cells with normal forms of huntingtin protein had a dramatically different methylation pattern to cells with mutant forms. Some stretches of DNA had lost methylation, while others had gained it. They also noted that most of the sites affected were in regions of the genome that control the switching on and off of neighbouring genes responsible for the growth and survival of brain cells. It appears that the mutant form of huntingtin specifically targets genes involved in brain function, says Fraenkel, who speculates it could be disruptions in those genes that account for the brainwasting symptoms characteristic of Huntington’s disease, including early changes in cognition. After noticing the differences in methylation patterns, the team also identified many of the proteins that would bind to the sites involved, including Sox2, and other genes known to control genes involved in brain cell growth and behavior.