Sequestered prion protein takes the good mood away, suggests new hypothesis on depression

The discovery of antidepressant drugs in the 1950s led to the first biochemical hypothesis of depression, known as the monoamine hypothesis. This hypothesis proposes that an imbalance of certain brain chemicals is the key cause of depression. Research has investigated whether and to what degree the "reward and pleasure" chemical dopamine and, more recently, the "happiness" chemical serotonin, could be the neurotransmitters involved in the malady. However, the monoamine hypothesis does not seem to fully explain the complexity of human depression. Now a new study offers one more important key that may increase our understanding of the pathogenesis behind clinical depression and neurodegenerative disorders.

Proteinaceous infectious particles, also known as prions, are proteins in which the complex molecular three-dimensional folding process has simply gone astray. For reasons not yet understood, the misfolding nature of prions is associated to their ability to sequester their normal counterparts and induce them to misfold as well. The ever-growing crowd of misfolded proteins form the aggregates seen in the brains of patients with neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Patients with these disorders manifest progressive neurological deterioration and clinical depression, among other symptoms.

Although the misfolded counterparts have historically received all the attention, the spotlight is now on the native protein, namely the prion protein, which is the one that has not undergone misfolding.

What role do the native proteins play? An interesting hypothesis is that these particles serve as a hub where some cellular components assemble. For instance, it has already been shown that the prion protein participates in events such as cell proliferation, differentiation and survival. Now a team led by Dr. Rafael Linden from the Institute of Biophysics Carlos Chagas Filho, at the Federal University of Rio de Janeiro, in Brazil, proposes that the prion protein plays a role in depression.

What is depression?

Sadness or downswings in mood are normal reactions to life’s struggles, setbacks, and disappointments. Many people use the word “depression” to explain these kinds of feelings, but depression is much more than just sadness.

Some people describe depression as “living in a black hole” or having a feeling of impending doom. However, some depressed people don't feel sad at all—they may feel lifeless, empty, and apathetic, or men in particular may even feel angry, aggressive, and restless.

Whatever the symptoms, depression is different from normal sadness in that it engulfs your day-to-day life, interfering with your ability to work, study, eat, sleep, and have fun. The feelings of helplessness, hopelessness, and worthlessness are intense and unrelenting, with little, if any, relief.

In an article entitled "" and published in the Journal of Biological Chemistry, the group shows that mice lacking normal prions show a depressive-like behavior similar to depression symptoms found in patients with Alzheimer's and prion diseases, namely Creutzfeldt-Jakob Disease (CJD), variant Creutzfeldt-Jakob Disease (vCJD), Gerstmann-Sträussler-Scheinker syndrome, Fatal Familial Insomnia and kuru. Human prion diseases frequently show clinical symptoms such as depression, anxiety, and hallucinations, and the monoamine hypothesis has been called to explain such deficits.