Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations on the methyl CpG binding protein 2 (MECP2) gene located on the X chromosome. MECP2 plays a vital role in brain development. Mutations in MECP2 cause severe cognitive, sensory, motor, and emotional impairments in individuals living with Rett syndrome. RTT is the 2nd leading cause of intellectual disability in women. However, there is currently no drug treatment available for RTT, so research into better understanding RTT and its associated mutations in MECP2 is very important.
In the article “mGlu7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome”, Dr. Rocco G. Gogliotti and colleagues found that mouse models of RTT show deficits in long term potentiation (LTP) at specific synapses in the hippocampus caused by the mutation in MECP2. They were able to show that metabotropic glutamate receptor 7 (mGlu7 ) expression is reduced in the total cortex and the hippocampus in mouse models with a MECP2 mutation and in humans with RTT. The researchers found that metabotropic glutamate receptor 7 (mGlu7) is the predominant receptor expressed presynaptically at these impaired synapses at the hippocampus. mGlu7 activation is necessary for LTP to occur in this area, so the researchers wanted to see if inducing increased potentiation in mGlu7 would treat RTT phenotypes in mouse models. The researchers were also able to show that by using two group III mGlu receptor PAMs, they were able to increase potentiation at mGlu7 mediated synapses in the hippocampus, which effectively rescued these synapses. The effect of these PAMs also rescued RTT phenotypes including learning and memory deficits, social preference and anxiety and apenas. The results of this study show that reactivation of impaired neurons found in RTT is a good target for possible treatment of the disorder.
Dr. Rocco G. Gogliotti’s study provided a better insight into how mutated MECP2 affects other genes and the neurons and synapses in models of RTT. However, a possible drug that targets these neurons has yet to come around. An article published by Science Daily spoke about a recent study led by Dr. Manel Esteller in which they are looking at another possible drug treatment that targets the neuroinflammation that is seen in Rett syndrome. The researchers were able to show that glycogen synthase kinase-3B (GSK3B), an important neuroinflammatory protein, is over expressed in mouse models of RTT. GSK3B is important for neural and synapse development and neural growth, so the researchers believe it plays a role in the phenotypes of RTT. They decided to test the effects of a drug that acted as an inhibitor of GSK3B on mouse models of RTT. The study used the agent SB216763 (a GSK3B inhibitor), and found that mice with RTT that were treated with this drug lived longer, and it significantly reduced RTT phenotypes such as mobility impairments, apenas and tremors. Inhibition of GSK3B also led to improvement at the molecular level of neurons. As was seen in Dr. Rocco G. Gogliotti’s study, treatment of SB216763 in RTT mice caused increased potentiation in impaired neurons which improved neuronal communication and their synapses and improved their denetric network. The results of this study provide promising evidence for a possible drug treatment for RTT.
The results of both Dr. Rocco G. Gogliotti and Dr. Manel Esteller studies provide great insight into how the mutation of MECP2 seen in RTT affects other genes and how that translates into various impairments in the brain. However, much is still unknown about the role MECP2 plays in the brain of patients with RTT. It is clear more research is needed to understand this role and explore possible drug treatments further. Future experiments could focus on how the results from these mouse model studies translate into humans living with RTT and how the drugs like the one used in Dr. Manel Esteller’s study would work when looking at a human brain instead of a mouse brain.
Works Cited:
IDIBELL-Bellvitge Biomedical Research Institute. "A new drug shows preclinical efficacy in Rett syndrome." ScienceDaily. ScienceDaily, 14 May 2018. <www.sciencedaily.com/releases/2018/05/180514122503.htm>.
Olga C. Jorge-Torres et al. Inhibition of Gsk3b reduces NFk-B signaling and rescues synaptic activity to improve the Rett syndrome phenotype in Mecp2-knockout mice. Cell Reports, 2018 DOI: 10.1016/j.celrep.2018.04.010
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