Revealing the molecular mechanism of common gene mutations leading to amyotrophic lateral sclerosis
September 1, 2015 Source: Health sickness
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];The researchers said that mutations interfere with RNAs and protein entry and exit in the nucleus. This study shows that common gene mutations in ALS and FTD block the transmission of information, causing neurons in the brain and spinal cord to be in a stage of degeneration and death; A few years ago, the researchers identified a mutation called C9ORF72, and now researchers have found that mutations in C9ORF72 are responsible for the initiation of ALS, and mutations in the C9ORF72 gene also cause FTD.
Dr. J. Paul Taylor said that until now, researchers believe that mutations in the C9ORF72 gene are the most common genetic deletions associated with the pathogenesis of ALS and FTD, so understanding the molecular mechanisms underlying this mutation can block or reverse patients with late-stage development of new therapies. The death of neurons in the brain and spinal cord provides new hope.
In the United States, nearly 5,600 individuals are diagnosed with ALS each year, and more than 90% of them have no family history of disease. The mutation of gene C9ORF72 accounts for 4% to 6% of ALS patients, but has a family history. The proportion of patients accounted for 25% to 40%. Normally, the gene C9ORF72 contains an exercise DNA with 20 repeats or fewer repeats, and in the mutated gene, the sequence GGGGCC will expand and abnormally repeat dozens or even thousands of times, and the RNA produced will be repeated. The RNA and protein that ultimately cause abnormal shape of the damaged cells.
To determine if this duplication affects cells, the investigator Brian Freibaum developed a Drosophila model of ALS and FTD. The model includes the C9ORF72 gene with multiple repeats, compared to a normal repeat number of fruit flies. Drosophila with 58 sequence repeats often have severe disease symptoms; the researchers then screened more than 80% of the mutant Drosophila genome to track the consequences of C9ORF72 gene sequence repeats.
By successively knocking out each gene, the researchers identified 18 modified genes, and the loss of these genes caused symptoms to be alleviated or aggravated, and these 18 genes also participated in the nuclear transport process. The researchers said that examining neurons produced in patients with mutations in the C9ORF72 gene may reveal the RNA composition in the nucleus. When the researchers compared the intracellular and extranuclear RNA concentrations, they found that compared to individuals who did not carry mutations. In other words, the density of RNA in the neurons of patients carrying mutations is higher than that of the former by 35%. The study included analysis of neurons produced by five patients carrying the C9ORF72 mutation, which did not affect the same patient's body. The RNA concentration of skin fibroblasts has a similar effect, so this suggests that the damage caused by the mutation of the gene C9ORF72 may be limited to the brain.
Finally, the researcher Taylor said that we will continue to study in the later stages to determine why this newly identified gene deletion has toxic effects on neurons, and researchers need to reverse this deletion in late therapy, such as blocking or silent mutations. Gene expression, the researchers believe that more in-depth research or will help develop new therapies for the treatment of ALS and FTD.
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