Two approaches to discovering possible treatments for Rett Syndrome

    This semester, Dr. Rocco Gogliotti from Loyola’s Stritch School of Medicine spoke to us about his research on a mouse model of Rett syndrome, an X-linked disorder which leads to seizures, cognitive impairments, apneas, and other motor deficits. In his presentation, Dr. Gogliotti dissected his paper, “mGLU7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome,” and explained the implications of mGLU7 receptor in the development of Rett syndrome. By investigating brain cells of deceased patients, Dr. Gogliotti found that patients who had Rett syndrome had a mutation in Methyl-CpG binding protein 2 (MECP2) and a subsequent muted mGLU7 expression, suggesting that MECP2 is an activator of mGLU7. The causality of this relationship was confirmed through mice experiments, with results showcasing that a loss of MECP2 impairs the function of the protein mGLU7 at hippocampal synapses. Further results showed that increased mGLU7 may actually lead to long-term potentiation in hippocampal and cortical regions and decrease the phenotypes of RTT syndrome. These results are both fascinating and promising, suggesting that potentiation of mGLU7 may be an effective treatment method for cognitive and respiratory deficits caused by RTT

    At this point of research advancement, it has been established that MECP2 mutations cause the development of Rett syndrome, as Dr. Gogliotti’s research corroborated. However, the approach that researchers have taken to reduce the implications of this mutation has varied. While Dr. Gogliotti focused on the expression of mGLU7 receptor, Dr. In-Hyun Park at Yale University’s Child Study Center and Stem Cell Center examined the relationship between MECP2 mutations and the BRD4 chromatin binding gene. By using a human brain organoid with a MECP2 mutation built from embryonic stem cells, Dr. Park and colleagues found that mutations of MECP2 lead to severe abnormalities, particularly in interneurons. Because interneurons are important in inhibition, regulation, and neuronal communication, the loss of interneuron function leads to the neurological issues presented in patients with Rett syndrome. Furthermore, the researchers found that interneurons with mutated MECP2 had elevated BRD4 binding. This maintained the interneurons in a hyperactive transcription state, which led to dysregulation of neural development genes.

    After reaching these conclusions from human brain organoids, Dr. Park and colleagues sought a potential treatment. Testing in vivo, the researchers found that a low dose of JQ1, an experimental cancer drug, corrected the abnormalities in the interneurons of mice with a Rett syndrome model. This is due to JQ1’s function, which reduces the number of dysregulated genes that result from MECP2 mutations and BRD4 augmented binding and subsequent hyperactive transcription. Interestingly, a low dose was helpful, whereas a high dose of JQ1 led to memory impairments. Furthermore, the mice that received the treatment lived about twice as long as those not receiving the drug. Thus, Dr. Park’s findings indicate that the transcription mechanisms of BRD4 are implicated in the development of Rett syndrome phenotypes, which may be reversed by targeting BRD4 using JQ1

    The work of both Dr. Park and Dr. Gogliotti focused on finding a target for treatment of Rett syndrome phenotypes. However, there are notable differences in their approaches and methods. While Dr. Gogliotti target mGLU7 after concluding that MECP2 is an activator of the glutamate receptor, Dr. Park targeted a gene involved in chromatin binding, BRD4. Further, Dr. Gogliotti closely examined hippocampal and cortical synapses, whereas Dr. Park investigated interneurons. Their differences in targets show that there are various pathways to reach a treatment method for Rett syndrome. Additionally, Dr. Park examined the interneurons in a human brain organoid prior to conducting an in vivo experiment on mice, whereas Dr. Gogliotti first looked at brain cells of patients who had Rett syndrome, then utilized mouse models to specify the effect of mGLU7. Although the researchers differ in their approaches, they both advanced basic knowledge of the causality behind a fatal disease and propose targets for intervention. Using this literature and other studies, researchers are continuing to apply findings into developing needed potential treatment for Rett syndrome.

 

Citations:

 

Gogliotti, R.G., Senter, R.K., Fisher, N.M., Adams, J., Zamorano, R., Walker, A., Blobaum, A.L., Engers, D.W., Hopkins, C.R., Danielle, J.S., Jones, C.K., Lindlsey, C.W., Xiang, Z., Conn, P.J., & Niswender, C.M. (2017). mGLU7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome. Science Translational Medicine. 9(403). 

Hathway, B. (2020, July). Yale researchers find potential treatment for Rett Syndrome. Yale News.

Park, I.H., Xiang, Y., Tanaka, Y., Patterson, B., Hwang, S.M., Hysolli, E., Cakir, B., Kim, K.Y., Wang, W., Kang, Y.J., Clement, E.M., Zhong, M., Lee, S.H., Cho, Y.S., Patra, P.,    Sullivan, G.J., & Wessiman, S. (2020, July). Molecular Cell Jounral. 79(1), 84-98.