Mad Cow Disease Protein May Play A Role In Depression

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Stigma may continue to prevail, but depression remains the most common mental illness worldwide, affecting some 350 million people. While treatable, there is still considerable confusion over its origins. In all likelihood, there is no single cause, but one of the leading ideas is that it results from an imbalance of chemicals in the brain, namely the “happy” hormone serotonin and the “pleasure” hormone dopamine.

But even if faulty chemistry is involved, it is insufficient to fully explain depression’s sheer complexity, and there is lingering uncertainty over whether the apparent chemical dysregulation is in fact a cause or instead a symptom. While the jury’s still out, scientists may have just discovered another contributing factor – abnormal bundles of proteins called prions – that could further our knowledge not only of depression, but other brain disorders in which these proteins are already implicated, like Alzheimer’s.

You may already be familiar with the term prion as these bizarre entities are the cause of a group of horrific neurodegenerative conditions known as transmissible spongiform encephalopathies, including the well-known diseases BSE and CJD. But what you may not know is that prions are actually made up of a protein, named the prion protein, which is found throughout the body on nerve and immune cells. Although not essential to life, this normal protein does play a role in a variety of cellular events, like cell proliferation and survival.  

While part of our makeup, there is a sinister side to prion proteins: They can contort themselves into the wrong shape. Sounds innocuous, but once they get into a twist, they trigger a domino effect whereby they round up their neighbors and coax them into following suit. These misbehaving protein crowds are toxic to cells and prevent them from functioning normally, a condition observed in the brains of patients with numerous neurodegenerative diseases, including Alzheimer’s and Parkinson’s.

So we know prions are bad for our brains, but what about their constituent, the prion protein? Mounting evidence suggests that it may serve as an assembly hub for signaling molecules involved in an array of physiological functions, but more importantly, it also seems to be involved in the transmission of chemicals, or neurotransmitters, between nerve cells. Furthermore, the levels of these chemicals, including serotonin and dopamine, have been observed in patients with CJD, many of whom also display symptoms of severe depression.

In an attempt to tie these links together, scientists engineered mice so that they were lacking the prion protein and observed them during a series of tests. As described in the Journal of Biological Chemistry, when compared to control mice, these animals displayed depressive-like behavior and had markedly increased levels of serotonin receptors, alongside more dopamine and the enzyme that produces it. Although dopamine receptor levels seemed to be unaffected, the cascade of events that typically ensue after dopamine binds to its receptor did not seem to occur.

“It is possible that the lack of interaction between dopamine and its receptor results from a desensitization of the receptor precisely because there is too much dopamine,” lead author Danielle Beckman explains.

Lending further weight to the idea that prion proteins are involved in depression, the team also found that their location in the brain overlapped with that of dopamine and serotonin receptors. And tantalizingly, preliminary findings suggest that the prion protein may interact with the dopamine receptor.

Taken together, the researchers propose a possible mechanism for the involvement of prion proteins in depression, suggesting that when they begin to misfold and aggregate, they are no longer able to serve as a platform for the assembly of molecules involved in neurotransmitter signaling, thus ultimately altering mood. The researchers hope these new findings could lead to novel, targeted treatments for depression and other mood disorders. 

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