Brain protein influences how the brain manages stress; suggests new model of depression

Credit: Rice University

The brain's ability to effectively deal with stress or to lack that ability and be more susceptible to depression, depends on a single protein type in each person's brain, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published November 12 in the journal Nature.

The Mount Sinai study findings challenge the current thinking about depression and the drugs currently used to treat the disorder.

"Our findings are distinct from serotonin and other neurotransmitters previously implicated in depression or resilience against it," says the study's lead investigator, Eric J. Nestler, MD, PhD, Nash Family Professor, Chair of the Department of Neuroscience and Director of the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai. "These data provide a new pathway to find novel and potentially more effective antidepressants."

The protein involved in this new model of depression is beta-catenin (B-catenin), which is expressed throughout the brain and is known to have many biological roles. Using mouse models exposed to chronic social stress, Mount Sinai investigators discovered that it is the activity of the protein in the D2 neurons, a specific set of nerve cells (neurons) in the nucleus accumbens (NAc), the brain's reward and motivation center, which drives resiliency.

Specifically, the research team found that animals whose brains activated B-catenin were protected against stress, while those with inactive B-catenin developed signs of depression in their behavior. The study also showed suppression of this protein in brain tissue of depressed patients examined post mortem.

"Our human data are notable in that we show decreased activation of B-catenin in depressed humans, regardless of whether these individuals were on or off antidepressants at the time of death," says the study's co-lead investigator, Caroline Dias, an MD-PhD student at the Icahn School of Medicine at Mount Sinai. "This implies that the antidepressants were not adequately targeting this brain system."

In the study, researchers blocked B-catenin in the D2 brain cells in mice that had previously shown resilience to depression and found the animals became susceptible to stress. Conversely, activating B-catenin in stress mice bolstered their resilience to stress.

Nearly all nerve cells in the NAc brain region are called medium spiny neurons. These cells are divided into two types based on how they detect the neurotransmitter dopamine, which is important in regulating reward and motivation. One type of neuron detects dopamine with D1 receptors and the other with D2 receptors. The Mount Sinai data specifically implicate the D2 neurons in mediating deficits in reward and motivation that contribute to depression or enhancements that mediate resilience.

Examining the genes regulated by B-catenin, the team then traced the pathway that was engaged when B-catenin was activated in the D2 neurons and discovered a novel connection between the protein and Dicer1, an enzyme important in making microRNAs, small molecules which control gene expression.

"While we have identified some of the genes that are targeted, future studies will be key to see how these genes affect depression. Presumably, they are important in mediating the pro-resilient effects of the B-catenin-Dicer cascade," says Dr. Dias.

While the molecular underpinnings of depression have remained elusive despite decades of research, the new Mount Sinai study breaks new ground in understanding depression in three important ways. It is the first report that B-catenin is deficient in nucleus accumbens in human depression and mouse depression models; it is the first study to show that higher activity of B-catenin drives resilience and the first report demonstrating a strong connection between B-catenin and control of microRNA synthesis.

The findings also suggest that future therapy for depression could be aimed at bolstering resilience against stress.

"While most prior efforts in antidepressant drug discovery have focused on ways to undo the bad effects of stress, our findings provide a pathway to generate novel antidepressants that instead activate mechanisms of natural resilience," says Dr. Nestler.

 

Provided by The Mount Sinai Hospital 

http://health.einnews.com/article/234538918/0pWYIINJjNOGC7mB?n=2&code=ga_qGBxHZ2aVYO4P

Scientists make breakthrough in understanding Parkinson's disease

Parkin-expressing cells (red) are undergoing programmed cell death. Credit: Dr Emilie Hollville and Professor Seamus Martin, Trinity College Dublin

Scientists at Trinity College Dublin have made an important breakthrough in our understanding of Parkin - a protein that regulates the repair and replacement of nerve cells within the brain. This breakthrough generates a new perspective on how nerve cells die in Parkinson's disease. The Trinity research group, led by Smurfit Professor of Medical Genetics, Professor Seamus Martin, has just published its findings in the internationally renowned, peer-reviewed Cell Press journal, Cell Reports.

Although mutation of Parkin has been known to lead to an early onset form of Parkinson's for many years, understanding what it actually did within cells has been difficult to solve. Now, Professor Martin and colleagues have discovered that in response to specific types of cell damage, Parkin can trigger the self-destruction of 'injured' nerve cells by switching on a controlled process of 'cellular suicide' called apoptosis.

Using cutting-edge research techniques, the Martin laboratory, funded by Science Foundation Ireland, found that damage to mitochondria (which function as 'cellular battery packs') activates the Parkin protein, which results in one of two different outcomes - either self-destruction or a repair mode. Which outcome was chosen depended on the degree of damage suffered by the cellular battery packs.

Importantly, these new findings suggest that one of the problems in Parkinson's disease may be the failure to clear away sick nerve cells with faulty cellular battery packs, to make way for healthy replacements. Instead, sickly and dysfunctional nerve cells may accumulate, which effectively prevents the recruitment of fresh replacements.

Commenting on the findings, Professor Martin stated: "This discovery is surprising and turns on its head the way we thought that Parkin functions. Until now, we have thought of Parkin as a brake on cell death within nerve cells, helping to delay their death. However, our new data suggests the contrary: Parkin may in fact help to weed out injured and sick nerve cells, which probably facilitates their replacement. This suggests that Parkinson's disease could result from the accumulation of defective neurons due to the failure of this cellular weeding process."

Professor Martin also added: "We are very grateful for the support of Science Foundation Ireland, who funded this research. This work represents an excellent example of how basic research leads to fundamental breakthroughs in our understanding of how diseases arise. Without such knowledge, it would be very difficult to develop new therapies."

Parkin-expressing cells (red) are undergoing programmed cell death. Credit: Dr Emilie Hollville and Professor Seamus Martin, Trinity College Dublin

http://health.einnews.com/article/234538918/v-AWr8PJ31SOWdCT?n=2&code=ga_qGBxHZ2aVYO4P

Good News! How Parkinson's Patients May Soon Regain Control

Parkinson's patients may soon have a new treatment. Scientists have successfully used stem cells to replaced damaged neurons. Photo courtesy of Shutterstock

Parkinson’s disease patients can find hope in a new treatment, thanks to breakthrough stem cell research that successfully replaces damaged nerves. Swedish researchers have figured out how to create motor neurons that become lost in the brains of Parkinson’s disease patients. They published their findings in the journal Cell Stem Cell.

Researchers from Lund University took human embryonic stem cells (hESC) from in vitro fertilization embryos and grew them into motor neurons. The neurons were transplanted into the brains of rats with Parkinson’s disease, and over the course of five months, their dopamine levels rose back to normal. There are currently one million individuals living with Parkinson’s disease in the United States, and 96 percent of them were diagnosed after the age of 50.  

Parkinson’s is an incurable progressive disease that takes over your body, rendering you without control, according to the Parkinson’s Disease Foundation. It affects the nervous system and movement, causing tremors, stiffness, slow movements, impaired posture and balance, speech changes, and other life-changing symptoms. This tumbling loss of motor skills is partially caused by the death of nerve cells that control dopamine in the brain. Researchers don’t know exactly why the chemical messenger begins to die, but once dopamine levels decrease, the brain loses the ability to regulate critical muscle movements.

"Our study represents an important milestone in the preclinical assessment of hESC-derived dopamine neurons and provides essential support for their usefulness in treating Parkinson's disease," said the study’s lead author Malin Parmar of Lund University, in a press release.

There are medications available for Parkinson’s patients, however, none have been able to successfully reverse the effects of the disease. This research is only the first step toward new treatment, but it's a huge and important finding in Parkinson’s disease research. Scientists still need to see if they can reverse Parkinson’s symptoms in animals on a long-term basis. Then, they need to see if they can replicate their findings in humans. If laboratory testing passes in the future, researchers may be able to use tissue from aborted human fetuses — one of the few options, since there's a limited availability of cells. This would help make stem cell replacement a realistic and therapeutic option for Parkinson’s patients who need enough hESC to make the treatment effective.

Roger Barker, of Addenbrooke’s Hospital and the University of Cambridge, reviewed the study and warned that the researchers must be thorough in their process, without rushing into clinical testing. "This involves understanding the history of the whole field of cell-based therapies for Parkinson's disease and some of the mistakes that have happened," Barker said. "It also requires a knowledge of what the final product should look like and the need to get there in a collaborative way without being tempted to take shortcuts, because a premature clinical trial could impact negatively on the whole field of regenerative medicine."

Source: Parmar M, Grealish S, Diguet E, Kirkeby A, Mattsson B, and Heuer A, et al. Human ESC-Derived Dopamine Neurons Show Similar Preclinical Efficacy and Potency to Fetal Neurons when Grafted in a Rat Model of Parkinson’s Disease. Cell Stem Cell. 2014.

http://www.jewishworldreview.com/1114/How_Parkinsons_Patients_May_Soon_Regain_Control.php3#CrgJ4amHE4vioUuV.99