In Fall 2017, PRISMS was honored to announce the award of $150,000 to Dr. Shigeki Iwase and Dr. Michael Sutton at the University of Michigan to support their research into the “Roles of RAI1 in Translating the Histone Methylation Code into Synaptic Plasticity.”

This grant funded a post-doctoral fellow, Takao Tsukahara D.D.S Ph.D, from January 2018 to March 2020. With support from his mentors in the Iwase and Sutton labs, Takao has been working on projects to increase our understanding of the function of RAI1, the gene that is the underlying cause of Smith-Magenis Syndrome.

We are thrilled to share the results of Dr. Tsukahara’s work so far with our community. Please see below for a summary of the findings he has made as PRISMS funded post-doc.

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Takao Tsukahara D.D.S Ph.D
Drs. Iwase and Sutton Laboratories
University of Michigan

Just like the human body’s temperature is maintained around 36-37C°, the neural network of the human brain also has a set point for activity where it functions optimally. The neural network is capable of dynamically changing its level of activity in response to environmental stimuli, and does so regularly. However, if this increased or decreased network activity is not buffered, the overall neural network can be destabilized, which leads to pathological states such as epilepsy. Therefore, the ability of the neural network to stabilize its activity back to its set point is critical for proper brain functioning. Destabilized neural network activity is a common feature of neurodevelopmental disorders such as Smith Magenis Syndrome (SMS). Because of this, the first focus of our research was to determine if RAI1, the causal gene of SMS, is involved in stabilizing neural network activity.

Indeed, we found that RAI1 plays a crucial role in a mechanism that maintains network activity by regulating the gene expression program that adjusts synaptic strength. During this project, we also found that the expression of genes involved in the sleep-wake cycle were highly altered when the presence of RAI1 was reduced. If the observed deficits in the ability to alter synaptic strength was the consequence of aberrant expression of sleep-wake cycle genes induced by loss of RAI1, restoring the proper expression of those genes could not only ameliorate the abnormal sleep-wake cycle in SMS but also attenuate other brain functions. Therefore, this finding opens the possibility that interventions that focus on sleep-wake cycle genes could be a potential strategy for treating SMS patients. We are now testing this hypothesis by manipulating sleep-wake cycle gene expression in rodent cultures with RAI1 reduction.

As another project, we are screening the enzymes that place or remove methylation at the 4th lysine residue of the histone H3 protein (H3K4me), a hallmark of a transcriptionally active area in the genome, in their roles in altering synaptic strength. Given that RAI1 somehow reads this chemical code and mutations in 9 of 12 H3K4me enzymes are associated with neurodevelopmental disorders, there is a possibility that some or one of H3K4me enzymes share common pathways with RAI1. So far, we have assessed all six enzymes that place methylation and found that two enzymes have a function similar to RAI1 in regulating synaptic strength. Another two of these enzymes have an opposing function to RAI1 in regulating synaptic strength. We are further looking at the gene expression program regulated by these enzymes and continuing the screening of the enzymes that remove methylation. We expect this work will deepen our understanding of RAI1’s functional pathway and possibly identify other candidates for therapeutic intervention in SMS patients.

Together, we believe our research will contribute to provide a solid ground for developing an efficient therapeutic strategy for treating SMS. Projects are continuing!

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