New genetic screening for Huntington's disease

New genetic screening for Huntington's disease

Huntington's disease is a genetic disorder that is debilitating and progressive, leading to severe brain damage and eventual death. Patients with this autosomal dominant disorder have a protein called huntingtin protein that forms clumps in the brain that lead to the symptoms of the disease.

Researchers at MIT have developed a way to perform genetic screening that could help identify the genes that predict neuronal survival. Their screening method was expanded to detect the genes that cause the mutant protein huntingtin to form and damage the brain. The results of this new study were published in the latest issue of the journalNeuron.

A genome-wide analysis has discovered genes essential for the survival of neurons, as well as genes that protect against the effects of Huntington's disease. Image source: Romanova Natali / Shutterstock

According to the researchers, while they were able to identify the genes responsible for the appearance of the mutated protein, it also led to a drug target that, if pursued, could lead to a possible treatment for the fatal and incurable Huntington's disease. Myriam Heiman, associate professor of neuroscience in the Department of Brain and Cognitive Sciences, who led the study, said, "These genes have never before been linked to the processes of Huntington's disease." When we saw them, it was very exciting because we found not just one gene, but actually several of the same family, and we also saw that they had an effect on two models of HD.” She is also a member of MIT's Picower Institute for Learning and Memory and the Broad Institute of MIT and Harvard. The study's lead author, Mary Wertz, is a postdoctoral fellow at the Broad Institute.

For this study, the team examined the genes that code for the proteins in the brains of mice. There are a number of around 22,000 genes, the researchers wrote. These genes could be studied for various neurological diseases, they explained. These included progressive neurological diseases such as Parkinson's and Alzheimer's, Heiman said.

According to the team, genetic screening is not new and is routinely performed on animals and study participants such as fruit flies, laboratory mice and the worm C. elegans after knocking out certain key genes in them. These screening tests examine lab subjects' ability to survive after important genes have been removed. This is the first study to conduct these tests on the brain of a mouse, the researchers wrote. They added that this is challenging because genetic changes in the brain are the most complex. Heiman said in a statement: "These unbiased genetic screens are very powerful, but the technical difficulty of performing them in the central nervous system at a genome-wide level has never been overcome."

Prior to this study, the team at the Broad Institute worked on genetic data libraries that could be used to study the results of removing one or more genetic sequences. Eventually, they came up with libraries that could selectively turn every gene on or off in the brains of mice. They used a special short hairpin RNA (shRNA) gene library to study messenger RNA, which carries vital information for protein synthesis. They used CRISPR to delete or edit the genetic sequences and used viral carriers to deliver the required altered genetic sequences within the cell.

The four or five shRNAs, or CRISPR segments, targeted each of the 22,000 mouse brain genes, using about 80,000 to 100,000 viruses to alter each of the brain cells in the mice. The viruses carrying the segments were sampled at high concentration and injected into the brain in the striatal region, and at least a quarter of all brain cells received at least one of the shRNA or CRISPR elements. The striatal region was more of a target because it deals with the body's motor system and helps with movement as well as cognitive functions and emotions. This area is affected not only by Huntington's disease, but also by autism, Parkinsonism and drug addiction.

The mice were continuously injected with virus carriers for seven months, after which the genetic make-up of the neurons in the stratum was checked. The neurons that needed the switched-off genes to survive would have died at the end of the study, the researchers explained. On the other hand, if non-essential genes were turned off, the neurons would be alive.

The results showed that several genes were important for neuronal survival. This also revealed several genes that are important for neuronal survival but were unknown in previous studies. Heiman said they discovered that certain genes were important that were not previously known to be important. She added: "We interpret this to mean that neurons in the mammalian brain are much more metabolically active and have a much greater dependence on these processes than, for example, a neuron in C. elegans."

They noted results in mouse models that produced a mutated form of the huntingtin protein. Screening of the normal mice was compared to those with Huntington's disease. If these mice contained lower levels of shRNA or CRISPR elements, they could be important targets that resisted the toxic effects of the huntingtin protein, Heiman explained. The team found that drugs targeting the Nme1 gene could be one such target.

Heiman concluded: "This is very exciting for us because in theory it is a druggable compound. If we can increase its activity with a small molecule, we may be able to reproduce the effect of genetic overexpression."
This study was supported by the National Institutes of Health (NIH), the National Institute of Neurological Disorders and Stroke (NINDS), and others.

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