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March 15, 2017

Anorexia Nervosa Modeled in a Dish, Risk Gene Uncovered

  • Although anorexia nervosa (AN) is often viewed as a nonbiological disorder, it is strongly suspected of having a genetic component, one that likely involves associations with multiple genes. These associations, however, appear to produce signals that are too faint to catch with the sort of genome-wide studies used thus far to evaluate AN. To enhance our sensitivity to AN's genetic signals, scientists based at the University of California San Diego School (UCSD) of Medicine have created a cellular model of the eating disorder. This model enabled the scientists to identify a gene, TACR1, that seems to contribute to AN pathophysiology.
     
    The new findings appeared March 14 in the journal Translational Psychiatry, in an article entitled "Modeling Anorexia Nervosa: Transcriptional Insights from Human iPSC-Derived Neurons." The article notes that although AN has the highest mortality among psychiatric conditions, it still lacks robust and effective treatment, largely because the cellular and molecular mechanisms underlying the disease remain obscure.
     
    In hopes of bringing these mechanisms to light, the UCSD team, led by Alysson Muotri, Ph.D., reprogrammed skin cells harvested from four females with AN and four healthy controls, induced these skin cells to become induced pluripotent stem cells (iPSCs), and differentiated the iPSCs into neurons.
    The resulting neural cultures were "subjected to extensive transcriptome analysis," wrote the article's authors. "Within a small cohort of patients who presented for treatment, we identified a novel gene that appears to contribute to AN pathophysiology, TACR1 (tachykinin 1 receptor)."
     
    The researchers explained that their unbiased comprehensive whole transcriptome and pathway analyses were arranged to determine not just which genes were being expressed or activated in AN neurons, but which genes or transcripts (bits of RNA used in cellular messaging) might be associated with causing or advancing the disease process.
     
    Although the researchers failed to observe predicted differences in neurotransmitter levels, they did succeed in detecting the disruption of the TACR1 gene. This finding led the researchers to speculate that tachykinins might interact with other neurotransmitters to disrupt the tachykinin system and contribute to AN symptoms.
     
    Tachykinins are neuropeptides or proteins expressed throughout the nervous and immune systems. These proteins participate in many cellular and physiological processes and have been linked to multiple diseases, including chronic inflammation, cancer, infection, and affective and addictive disorders.
     
    "Although TACR1 has been associated with psychiatric conditions, especially anxiety disorders, we believe this report is its first association with AN," the authors of the Translational Psychiatry article concluded. "Moreover, our human iPSC approach is a proof-of-concept that AN can be modeled in vitro with a full human genetic complement, and represents a new tool for understanding the elusive molecular and cellular mechanisms underlying the disease."
     
    "Anorexia is a very complicated, multifactorial neurodevelopmental disorder," commented Dr. Muotri. "It has proved to be a very difficult disease to study, let alone treat. We don't actually have good experimental models for eating disorders. In fact, there are no treatments to reverse AN symptoms.
    "[Our work is] a novel technological advance in the field of eating disorders, which impacts millions of people. These findings transform our ability to study how genetic variations alter brain molecular pathways and cellular networks to change risk of AN—and perhaps our ability to create new therapies."

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