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Understanding lithium key to treatments

Posted: 19th July 2018

Since Australian psychiatrist John Cade employed lithium to successfully treat one of his bipolar patients in the 1940s, scientists have tried, and largely failed, to understand why the treatment is so effective. The difficulty stems from the fact that lithium interacts with many proteins and other molecules in the brain, making it hard to determine which interaction is responsible for its mood stabilisation effects. This is also the root of lithium’s undesirable side effects.

Dr John Scott in SVI’s Protein Chemistry and Metabolism Unit became interested in the role of lithium because of his focus on the pathways that control energy usage in the body. His particular focus is a protein called Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2).

“CAMKK2 is one of the key steps along the pathway that leads to the activation of a protein called AMP-activated protein kinase, which acts as the body’s energy gauge. AMPK has been a focus of research in our Unit for decades,” says John.

“One way of dissecting the action of a protein is to look at the effects in people who have a genetic mutation in that gene. A couple of years ago we became interested in mutations in CAMKK2 in people who are affected by with behavioural disorders such as anxiety, bipolar and schizophrenia.”

John and his team showed that when they mimicked the human CAMKK2 mutation in the test-tube, the ability of CAMKK2 to activate the next step in the pathway was reduced.

Johns says, “We basically found a ‘switch’ in the protein that is normally able to be turned on and off. In people with a mutation in CaMKK2, this switch is permanently off. Excitingly, we were able to show that treatment with lithium could overcome the effects of the mutation.”

“Our hypothesis is that at least one of the ways that lithium works is by creating a bypass of the defective circuit, essentially leapfrogging the broken switch.”

In order to prove this hypothesis John needed to create a genetically modified mouse in which the CaMKK2 switch was mutated in a similar fashion. His goal was to show that this one isolated change would result in similar behavioural changes as seen in humans with the mutation.

In an environment where funding is so competitive, it has become more difficult to get funding to create mouse models of disease. John says that a grant where a model is already in hand is naturally a more compelling proposition to grant reviewers.

This is where the Angior Family Foundation stepped in. A grant from the Foundation in 2016 enabled John to do the work that he needed.

Thanks to the support, John has spent the last year examining the effects of the mutation on the behaviour of his mice. He is now a step closer to his goal of understanding how lithium works, with a longer term aim of developing safer and more effective therapies for debilitating mental disorders.

For more information please see: Protein chemistry & metabolism