The CRISPR technology to help find a cure for getting frozen human disease new targets

Source: the CRISPR technology to help find a cure for getting frozen human disease the new target point

Amyotrophic lateral sclerosis disease (amytrophic lateral sclerosis, ALS), commonly known as gradually frozen people disease, is a progressive and fatal neurodegenerative disease. Patients due to motor neurons progressively die, leading to muscle function degradation, like brushing your teeth, talking or even breathing such a simple muscle movement are ultimately not carried out. In the patient’s brain appears abnormal protein deposition is ALS an important sign of, but scientists are not aware of these protein deposits can lead to neuronal death. Recently,Stanford University (Stanford University) the researchers use CRISPR/Cas9 gene editing technology on the impact of ALS symptoms of the gene were screened, the findings not only help scientists further understand ALS pathogenesis, and for the treatment of ALS provides a new target pointit.

In ALS patients, a common cause is in the C90RF72 gene on the occurrence of six nucleotide repeat sequence amplification(hexanucleotide repeat expansion), to mutate the genes will Express very easy aggregation of dipeptide repeat(dipeptide repeat, the DPR) proteins. This DPR in cells of deposition is thought to lead to neuronal cell death causes.

The results, published in the Nature Genetics on the study, the researchers use CRISPR/Cas9 gene editing technology called K562 human cell lines for a genome-wide knockout screening (genome-wide knockout screens in). CRISPR technology is often used to modify the gene sequence, but in this study, it is used in the cells to make the human genome a specific gene inactivated. Then the researchers will DPR protein was added to the cell culture medium, the detection in a cell knock-out specific genes to allow them to DPR-induced cytotoxicity is more sensitive or generated resistant.

The researchers first in human cell lines of the human genome in all genes screened, they found several hundred genes to be able to DPR cytotoxicity with a positive or a negative impact. In order to with the ALS closer to the cell environment to test the functions of these genes, the researchers in the simulation of ALS mice neuronal cell culture model of the human cells in the DPR toxic effects maximum of about 200 genes were further detected.< strong>after two rounds of screening, the researchers found ten more genes of the DPR of cytotoxicity with maximum impactit.

In this more than a dozen genes, with several genes being knocked-out after the cells to produce a strong protective effect. For example, namedRBA7Agene is a lysosomal transport genes (endolysosomal trafficking gene), it may in the media DPR invade the cells and between the cells of the Ob to play an important role.

And another by researchers concerned gene isTmx2, when it is in the cell is a knockout, almost 100%of the cells in the DPR there is the environment to survive, and typically only 10%of the cells are able to survive.

“You can imagine the Tmx2 protein might be a good drug target,” the article’s first author, Stanford graduate student Michael Haney Mr. said:“if you have a small molecule compound able to by what method of inhibiting the Tmx2 function, then it is likely to become the treatment of ALS therapy。”

Tmx2 protein is in the cell the endoplasmic reticulum in a protein, its function has not been completely clarified. There have been studies that it may in the media the endoplasmic reticulum to the environment in the stress factor of the reaction plays an important role, in particular, is that it may trigger cell death. In this study, Stanford scholars believe that Tmx2 be able to adjust the other to start the cell death program of the gene.

“I think the understanding of the Tmx2 protein in the cells of normal function is the next problem to be solved, which will help us discover when the toxic protein to kill cells which function is affected, and that we should continue to examine which signaling pathways,” the article’s co-first author, Stanford graduate student Nicholas Mr. Kramer said.

While in this study the use of CRISPR screening techniques can be used to study other diseases in the signal path. Currently the study team is trying to use the same technique to study other due to the toxicity of the eggs���Deposition caused by neurodegenerative diseases, including Huntington’s disease(Huntington’s disease), Parkinson’s disease (Parkinson’s disease) and Alzheimer’s disease (Alzheimer’s disease).“ I think this is the CRISPR screening of a very exciting application, but it has only just begun,” the article’s senior author, Stanford genetics Professor Michael Bassik Dr. said.

References:

[1] Potential drug targets for ALS revealed in Stanford-led study using CRISPR

[2] The CRISPR–Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity

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Published at Sat, 10 Mar 2018 19:05:45 +0000