Biological engineers at Massachusetts Institute of Technology in the US have discovered that the gene that causes Huntington’s disease, a fatal neurodegenerative disorder, damages brain cell function by upsetting the on-off switching patterns of other genes. This detection will lead to ways of reinstating normal gene expression that can be used in treatments to slow or stop the evolution of the disease in early stages. The earliest phases of Huntington’s is most interesting, because that’s when there is large anticipation that one 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 improbable that one would be able to turn round the damage.
Huntington’s disease is a deadly neurodegenerative disorder. It is a genetic disease that characteristically hits in midlife and causes progressive death of specific areas of the brain. Most of the injury is to the basal ganglia, a part of the brain that is responsible for many functions, including intentional control of muscles and habit configuration. 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.
DNA carries directions 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 directives in the DNA. But a transcription protein can’t read a DNA instruction if the matching section of DNA is blocked. This is how genes can be “switched on and off,” forming complex pattern of gene expression that makes certain 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 related sections of DNA. There are genes that do this as a method to control when other genes are switched on and off.
Recently scientists comprehended that DNA methylation patterns aren’t fixed during embryonic development, but can change during an adult’s lifetime. In fact, it is an active process involved in a wide range of normal cell behavior.
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 the center for planning of movement and is severely affected by Huntington’s disease. The researchers found cells with normal forms of huntingtin protein had a different methylation pattern to cells with mutant forms. Some extended part of DNA had lost methylation, while others had gained it. They noted that most of the sites involved 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 seems like the mutant form of huntingtin exclusively targets genes involved in brain function disruption in those genes that explain the brain-wasting symptoms characteristic of Huntington’s disease, including early changes in cognition.
Noticing the differences in methylation patterns, the team 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. The question is how the changes to methylation actually produce the disease symptoms. These findings points to new treatment targets. One could imagine that if one can figure out, in mechanistic detail, what is causing these changes in methylation, one might be able to block this process and restore normal levels of transcription early on in the patients. Team is also finding out whether patterns of methylation change as the disease progresses.
In November 2012, researchers at the University of Montreal identified and “switched off” a chemical chain that caused neurodegenerative diseases such as Huntington’s disease, amyotrophic lateral sclerosis and dementia.