Cell model helped to find anorexia gene
Denis Strigun, Naked Science
An international team of scientists has created the first cellular model of anorexia nervosa and concluded that the disease is associated with a mutation of the TACR1 gene. The results of the work are published in the journal Translational Psychiatry (Negraes et al., Modeling anorexia nervosa: transcriptional insights from human iPSC-derived neurons).
The process of reprogramming fibroblasts and differentiation of iPSCs into neurons (here and below are the figures from the article in Translational Psychiatry).
To get around this problem, scientists from the University of California at San Diego and other institutions we have created a "cellular" model of the disorder in vitro. To do this, the authors reprogrammed the skin fibroblasts of four healthy women and four women with anorexia into induced pluripotent stem cells (iPSCs) using retroviral constructs and cloned them twice. The iSC was then placed in a neural induction medium and grown for seven days. The resulting neural progenitor cells (NPC) were differentiated into neurons of the cerebral cortex using an inhibitor of Rho-associated kinase (ROCK) and removal of the main fibroblast growth factor (bFGF). Four weeks later, the team received 16 "pure" neuronal cell lines from healthy women and patients with anorexia.
At the second stage, the researchers analyzed the gene expression and sequenced the RNA of the samples. Both indicators were compared with each other, as well as with 35,588 gene annotations common to ENSEMBL and HGNC annotation banks. In total, the authors transcribed 24,944 genes in neurons of both groups, 361 of which were differentially expressed. It is noteworthy that when considering only the genes associated with the development and differentiation of neurons, there were no statistically significant differences between the groups. Pronounced differences were also not revealed by immunochemical staining – according to scientists, this may indicate the absence of visible abnormalities in the brain of patients with anorexia nervosa.
The overall level of TACR1 expression, neuropeptides and the dynamics of TACR1 expression in different brain regions in the group of healthy women (CTL) and patients (AN).
Given that some neuropeptides and neurotransmitters can regulate human eating behavior, experts have also compiled a profile of these molecules. The analysis showed that the profile of neurotransmitters (for example, estrogen receptors) in the experimental and control groups was identical. However, the TACR1 gene in the neurons of the patients was overexpressed, whereas the expression of the TAC1 gene was almost halved in them. These genes encode the receptor and precursor of tachykinins – neuropeptides expressed in the nervous and immune systems, respectively. It is known that changes in tachykinin levels, in particular TACR1 mutations, are associated with various diseases, such as affective disorders and addictions. The authors of the new work also found that the peak of TACR1 expression in the striatum (regulates eating behavior) falls at puberty, with which the onset of anorexia is often associated.
Since many mental illnesses are considered multifactorial, genetic studies are important for understanding their etiology. Earlier, Russian scientists discovered a gene that is responsible for the development of depression in Europeans, and their American colleagues found a gene associated with distortion of tactile sensations in autism.
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15.03.2017