Q&A with Moses Chao, Ph.D.
Professor of Cell Biology, Physiology and Neuroscience, and Psychiatry

Many neurobiologists study receptors, molecules encoded by genes, which sit like small antennae on the surfaces of cells, including neurons in the brain. The outside part of these receptors is like a lock, which can be opened only by certain protein keys, or ligands. Once opened, these receptors activate a variety of internal signals throughout the nervous system. Neurotrophins spur nerve growth and are important for the overall survival of neurons. They are one of the molecules that dock on neuronal receptors in the brain. These molecules trigger a complex signaling pathway inside the cell that leads to the nucleus.

Neurotrophins like nerve growth factor (NGF) bind to receptors with enzymatic activity called tyrosine kinases, which add phosphate groups to proteins and set in motion internal cellular pathways. G protein-coupled receptors, another class, are most prevalent in the nervous system. In a recent study published in the Proceedings of the National Academy of Sciences, Dr. Chao and his collaborators show that neurotrophin receptors in damaged motor neurons in mice can be activated through a G protein-coupled receptor system by transactivation, or cross-talk. This observation could have wide-ranging implications in treating neurodegenerative diseases such as Parkinson’s and Alzheimer’s.

Q: You have had a long interest in neurotrophins.

A: Yes, I have been working on neurotrophins and their receptors for 20 years. Neurotrophins are very potent molecules. They were originally studied for their early developmental effects on the nervous system, and we now know that they have effects on the adult nervous system as well. We would like to take advantage of their signal transduction mechanisms to apply to neurodegenerative and psychiatric disorders.

Q: Why is the brain so resistant to treatment with nerve growth factors, which are supposed to protect neurons?

A: The previous attempts to use nerve growth factors in neurodegenerative diseases basically failed because of problems with delivery and numerous side effects that were encountered in clinical trials. Nerve growth factors are large, sticky proteins that do not diffuse very well, and their pharmacokinetics and their half-lives and dosages were not well understood. So that led to a lot of the initial problems in the efforts to use neurotrophins clinically.

Q: How widespread is this so-called cross-talk between unrelated neuronal receptors?

A:  That is a good question. I think it occurs between many different types of receptors. It probably does not approach the extent of signaling that happens with traditional ligand-receptor interactions. The original observations were between G protein-coupled receptors and the EGF [epidermal growth factor] receptor. But a number of other examples have now been reported. There is much potential for further studies because there are many drugs that target G protein-coupled receptors.

Q: How could cross talk be applied therapeutically?

A: Several of the ligands that bind to G protein-coupled receptors are small molecules. We think you can take advantage of these small ligands to cross-talk with neurotrophic receptors without having to use the natural neurotrophin proteins as ligands. In this way, you can bypass the problems of delivery across the blood-brain barrier and also the side effects of neurotrophins.

Q: Are there any drugs in development that are using cross-talk as a strategy?

A: I think many drugs use transactivation, or cross-talk, to trigger the activities of other receptors.  Several potential examples include steroids and antidepressants. 

Q: Is the small molecule used in your study easy to administer?

A: We have studied adenosine, a nucleoside, which is one of the building blocks of ATP [the main carrier of energy in the cell]. We found that adenosine binds to a specific G protein-coupled adenosine receptor and is capable of transactivating a neurotrophin receptor to provide neuroprotection to neurons that are destined to die.

Q: Is this study a jumping-off point for other studies?

A:  I think we have just scratched the surface. There are many G-coupled receptors, and there is a huge pharmacology with each receptor. We would like to be able to screen for additional molecules that cross-talk with trophic factor receptors. Receptors for adenosine are expressed in many organs. We also would like to identify small molecules that can target specific neurons in vulnerable regions of the brain relevant to neurodegeneration, such as Alzheimer’s and Huntington’s diseases.