Within PWS and general obesity research, there are several labs currently working in the area of serotonin signaling. Serotonin is a neurotransmitter and this pathway contributes to the regulation of appetite and mood, and is reported to be altered in PWS. Moreover, loss or alteration of the serotonin receptor 2C (HTR2c), has been associated with mood and appetite changes, including hyperphagia and obesity in mouse models.
The most recent FPWR newsletter highlighted the work of Dr. Kathryn Cunningham at the University of Texas Medical Branch (see blog), while this blog features a publication from a group led by Dr. Stefan Stamm at the University of Kentucky. Notably, FPWR research funds helped to support both of these projects (Dr. Cunningham; Dr. Stamm)!
While Dr. Cunningham’s work focuses on proteins that interact with the HTR2c protein and affect its function, Dr. Stamm is examining the role of RNA processing in HTR2c function. To understand the findings from Dr. Stamm’s group (Shen, 2013), a quick overview of the “Central Dogma” of genetics is helpful. This is the process by which genetic information ultimately results in complex biological function. Genetic information in the form of DNA is protectively stored in a special part of the cell (nucleus). When needed, a working copy of the information is made, resulting in RNA. The information in this RNA is a roadmap or key, which is then used to build proteins.
Although the basic process is from DNA→RNA→protein, there are many complex steps to each of these transitions. For example, there are a variety of processes that take RNA from its raw form (pre-mRNA) and prepare it in its final readable version (mRNA). One could think of this like a book editor taking a manuscript from its rough first draft to a publication ready format (removing, re-writing, and re-organizing text).
Although the DNA information for the HTR2c gene itself is not located on chromosome 15, one of the important processing systems for HTR2c pre-mRNA is found in the chromosomal region associated with PWS. This “snoRNA”, is SNORD115, also referred to as HBII-52. As shown in the schematic below, SNORD115 is critically involved in allowing the U1 processing pathway to interact with the HTR2c pre-mRNA which results in a fully functional serotonin receptor (pathway on left, diagram at bottom of post). Loss of SNORD115, as occurs in PWS, diverts HTR2c pre-mRNA down a secondary processing pathway (ADAR) and results in a less effective receptor (pathway on the right).
Dr. Stamm and his collaborators are working to identify drugs that will interact with the HTR2c pre-mRNA in such a way to change its shape and allow it to once again interact with the U1 processing system. In this way, they hope to use a drug to substitute for the normal function of the missing SNORD115 and generate a fully functional receptor, even in the absence of SNOD115. The HTR2c pre-mRNA is special, as it forms a defined and transiently stable structure in cells that allows other molecules to bind, and this property provides a basis to find a drug that might achieve their goal. To accomplish this, they performed a high-throughput screening of a chemical library of >1600 compounds and identified a compound, pyrvinium pamoate, that binds HTR2c pre-mRNA. As shown in the schematic, this rescues the ability of the HTR2c pre-mRNA to interact with the major RNA processing system U1 even in the absence of SNORD115, and likely leads to a fully functional receptor (pathway on left).
There is still much work to be done including confirmation of the effects of pyrvinium pamoate on HTR2c function, as well as studies in animals to demonstrate an effect of the drug on appetite and food intake. It is unlikely that this compound itself will result in a therapeutic due to 1) concerns over toxicity; and 2) undesired side effects from interacting with other pre-mRNAs. However, the results are an exciting proof of concept that drugs can potentially replace the function of missing snoRNAs in PWS, and provide a starting point to develop a drug that is suitable for human use.