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

August 13, 2015

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.

In an article entitled "Prion protein modulates monoaminergic systems and depressive-like behavior in mice" 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.

The research conducted by the group shows that mice with no prion protein have increased levels of the receptors that bind to serotonin. Additionally, the levels of the enzyme that makes dopamine, and dopamine itself, are also higher in mice deprived of the prion protein. Interestingly, the study shows that although these animals have high levels of dopamine, they do not show the normal response that should occur when dopamine binds to its receptor, despite the fact that the levels of the receptor for dopamine are normal in these animals. According to Danielle Beckman, the first author of the paper "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".

Another important observation made by the group, and which supports the hypothesis that prions have a role in depression, is the fact that the prion protein is found in the same places in the cell as the dopamine and serotonin receptors. Additionally, the authors observed that the prion protein might bind to the dopamine receptor.

The group believes that in normal individuals, the prion protein works as a scaffold for multiple molecular interactions. When prion protein molecules are sequestered by their misfolded counterparts, they can no longer work as a scaffold for all these molecular interactions, which impairs the mechanisms evoked by the brain chemicals important for mood.

These findings open the door for future research considering the prion protein as a potential target in the development of treatments for major depression and related disorders.
-end-
The online version of the paper can be found at http://www.jbc.org/content/early/2015/07/07/jbc.M115.666156.full.pdf+html

Publicase Comunicação Científica

Related Depression Articles from Brightsurf:

Children with social anxiety, maternal history of depression more likely to develop depression
Although researchers have known for decades that depression runs in families, new research from Binghamton University, State University of New York, suggests that children suffering from social anxiety may be at particular risk for depression in the future.

Depression and use of marijuana among US adults
This study examined the association of depression with cannabis use among US adults and the trends for this association from 2005 to 2016.

Maternal depression increases odds of depression in offspring, study shows
Depression in mothers during and after pregnancy increased the odds of depression in offspring during adolescence and adulthood by 70%.

Targeting depression: Researchers ID symptom-specific targets for treatment of depression
For the first time, physician-scientists at Beth Israel Deaconess Medical Center have identified two clusters of depressive symptoms that responded to two distinct neuroanatomical treatment targets in patients who underwent transcranial magnetic brain stimulation (TMS) for treatment of depression.

A biological mechanism for depression
Researchers report that in depressed individuals there are increased amounts of an unmodified structural protein, called tubulin, in lipid rafts compared with non-depressed individuals.

Depression in adults who are overweight or obese
In an analysis of primary care records of 519,513 UK adults who were overweight or obese between 2000-2016 and followed up until 2019, the incidence of new cases of depression was 92 per 10,000 people per year.

Why stress doesn't always cause depression
Rats susceptible to anhedonia, a core symptom of depression, possess more serotonin neurons after being exposed to chronic stress, but the effect can be reversed through amygdala activation, according to new research in JNeurosci.

Which comes first: Smartphone dependency or depression?
New research suggests a person's reliance on his or her smartphone predicts greater loneliness and depressive symptoms, as opposed to the other way around.

Depression breakthrough
Major depressive disorder -- referred to colloquially as the 'black dog' -- has been identified as a genetic cause for 20 distinct diseases, providing vital information to help detect and manage high rates of physical illnesses in people diagnosed with depression.

CPAP provides relief from depression
Researchers have found that continuous positive airway pressure (CPAP) treatment of obstructive sleep apnea (OSA) can improve depression symptoms in patients suffering from cardiovascular diseases.

Read More: Depression News and Depression Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.