In a new study published online in Biological Psychiatry on January 16, 2015, researchers from Butler Hospital identify an association between biological changes on the cellular level and both childhood adversity and psychiatric disorders. These changes in the form of telomere shortening and alterations of mitochondrial DNA (mtDNA), are important in the aging process, and this new research provides evidence that psychosocial factors–specifically childhood adversity and psychiatric disorders– may also influence these cellular changes and could lead to accelerated aging.
Mitochondria convert molecules from food into energy that can be used by cells and also play a key role in cellular growth, signaling, and death. Telomere shortening is also a measure of advanced cellular aging. Recent studies have examined the possible connection between mitochondria and psychiatric disorders, but the research is very limited, and no prior work has examined the relationship of mitochondrial DNA to psychosocial stress.
“We are interested in these relationships because there is now clear evidence that stress exposure and psychiatric conditions are associated with inflammation and health conditions like diabetes and heart disease. Identifying the changes that occur at a cellular level due to these psychosocial factors allows us to understand the causes of these poor health conditions and possibly the overall aging process.” said Audrey Tyrka, MD, PhD, Director of the Laboratory for Clinical and Translational Neuroscience at Butler Hospital and Associate Professor of Psychiatry and Human Behavior at Brown University.
Audrey R. Tyrka, Stephanie H. Parade, Lawrence H. Price, Hung-Teh Kao, Barbara Porton, Noah S. Philip, Emma S. Welch, Linda L. Carpenter. Alterations of Mitochondrial DNA Copy Number and Telomere Length with Early Adversity and Psychopathology.Biological Psychiatry, 2015; DOI: 10.1016/j.biopsych.2014.12.025
In a new study published in Applied Physiology, Nutrition, and Metabolism, scientists from the University of Guelph have found that exercise has the potential to decrease toxic build-up in the brain, reducing the severity of brain disorders such as Huntington’s disease.
Glutamate, an amino acid that is one of the twenty amino acids used to construct proteins, is used by the brain to transmit signals, but too much glutamate blocks future signals and can lead to toxicity in the brain. Since the majority of the brain relies on glutamate as the main neurotransmitter for communication between neural cells, it is essential that glutamate is reabsorbed and disposed of to prevent blockage. While glutamate reuptake is a normal process for healthy brains, several diseases such as Huntington’s disease, ALS, and epilepsy result in either failed reuptake of glutamate or high levels of glutamate in the brain. This can lead to unwanted and in some cases excessive stimulation of neighbouring cells which can worsen the disease.
The findings of this study show that exercise has the potential to increase the use of glutamate in the brain and may help reduce the toxicity caused by glutamate build-up in these diseases. “As we all know, exercise is healthy for the rest of the body and our study suggests that exercise may present an excellent option for reducing the severity of brain disorders” says Dr. Eric Herbst, lead author of the study. “Taking into account that there are no cures for neurodegenerative diseases where glutamate is implicated, this study offers another example of the benefits of exercise for our brains” continued Dr. Herbst. “In short, these findings offer another reason to exercise with the aim of either preventing or slowing the neurodegeneration caused by these disorders”.
The findings of this study are of particular importance to other researchers exploring different approaches to treating brain disorders. The main approaches to treating neurodegenerative diseases are hindered by the need to produce drugs that both have the intended effect for treating the disease and are also able to pass the blood brain barrier. Through the use of exercise, the brain can direct glutamate to be used as an energy source to dispose of excess amounts of the neurotransmitter, without relying on the difficult development of pharmaceuticals. Identifying and targeting the mechanisms that increase glutamate metabolism in the brain may also provide the medical field with additional ways of treating problems within the brain. How the findings of this study translates to people affected by neurodegenerative diseases still needs exploring and is an important next step.
Inside cells, organelles called mitochondria carry out a medley of vital tasks. These structures generate energy and help to keep the cells’ interior environment in a state of healthy equilibrium, among other functions.
Now, scientists show how a protein associated with Parkinson’s disease can damage these cellular powerhouses.
The findings come from experiments in which fruit fly larvae were genetically engineered to produce unusually high amounts of the protein, called alpha-synuclein.
“When fruit fly larvae expressed alpha-synuclein at elevated levels similar to what is seen in Parkinson’s disease, many of the mitochondria we observed became unhealthy, and many became fragmented. Through detailed experiments, we also showed that different parts of the alpha-synuclein protein seem to be responsible for these two problems, and that fragmented mitochondria can actually be healthy. This is a key finding, because before, people thought fragmented mitochondria were unhealthy mitochondria,” says Shermali Gunawardena, PhD, associate professor of biological sciences in the University at Buffalo College of Arts and Sciences.
The results could be of interest in the context of drug development, as abnormal aggregates of alpha-synuclein in brain cells are a hallmark of Parkinson’s disease, and mitochondrial damage has also been observed in patients.
“This research showcases the advantage of using fruit fly larvae as a model organism to study how neurons become damaged during devastating diseases such as Parkinson’s disease,” says TJ Krzystek, UB PhD candidate in biological sciences. “Through this approach, we pieced together a new understanding for how the Parkinson’s disease-related protein alpha-synuclein disrupts the health and movement of mitochondria — the epicenter for energy production in cells. We believe this work emphasizes a promising path that can be explored for potential therapeutics aimed at improving mitochondrial health in Parkinson’s disease patients.”
The co-first authors are Krzystek and Rupkatha Banerjee, PhD, a postdoctoral research associate at Scripps Research who completed her doctorate in biological sciences at UB. Gunawardena is the senior author.
The research was a collaborative effort, with many members of the Gunawardena lab making significant contributions. In addition to Banerjee, Gunawardena and Krzystek, the paper’s authors include undergraduates Layne Thurston, JianQiao Huang and Saad Navid Rahman, and PhD student Kelsey Swinter, all in the UB Department of Biological Sciences, and Tomas L. Falzone at the Universidad de Buenos Aires and Instituto de Investigación en Biomedicina de Buenos Aires.
A detailed look at alpha-synuclein and mitochondria
Through tests in fruit fly larvae, the scientists were able to tease out intricate details regarding interactions between alpha-synuclein and mitochondria.
For example, the study not only concludes that different sections of the alpha-synuclein protein are likely responsible for causing mitochondrial fragmentation and damaging mitochondrial health; the research also identifies these sections and describes how other proteins may interact with them to drive these changes. More specifically, the proteins PINK1 and Parkin — both linked to Parkinson’s disease — may interact with one end of alpha-synuclein to influence mitochondrial health, while a protein called DRP1 may interact with the other end to break mitochondria, scientists say.
“Mitochondrial impairments have long been linked to the pathogenesis of Parkinson’s disease,” Banerjee says. “However, the role of alpha-synuclein in mitochondrial quality control so far has not been comprehensively investigated. Our study unravels the intricate molecular mechanisms by which the different regions of alpha-synuclein exert distinct effects on mitochondrial health, bringing into light a potential pathway that could be targeted for exploring new therapeutic interventions in Parkinson’s disease.”
“We were able to tease out specific mechanistic functions for alpha synuclein by using imaging tools and a color-tagged marking system to observe the process of what happens to mitochondria when alpha-synuclein is elevated,” Gunawardena adds. “This system allowed us to observe the health, size and the movement behaviors of mitochondria at the same time in living neurons in a whole organism.”
(Image caption: Unhealthy mitochondria are marked in a gradient from white to red, with white being the least healthy, in contrast to healthy mitochondria that appear in blue. This still image is from a microscope video showing mitochondria moving in a fruit fly larval neuron expressing elevated levels of the protein alpha-synuclein. Credit: TJ Krzystek and Shermali Gunawardena)
“The current theory is widely accepted, but I would not say it is ‘established’ since nobody seems to have seriously considered alternative explanations,” explains David Baum, a University of Wisconsin-Madison professor of botany and evolutionary biologist who, with his cousin, University College London cell biologist Buzz Baum, has formulated a new theory for how eukaryotic cells evolved. Known as the “inside-out” theory of eukaryotic cell evolution, the alternative view of how complex life came to be was published recently (Oct. 28, 2014) in the open access journal BMC Biology.
The inside-out theory proposed by the Baums suggests that eukaryotes evolved gradually as cell protrusions, called blebs, reached out to trap free-living mitochondria-like bacteria. Drawing energy from the trapped bacteria and using bacterial lipids—insoluble organic fatty acids—as building material, the blebs grew larger, eventually engulfing the bacteria and creating the membrane structures that form the cell’s internal compartment boundaries.
“The idea is tremendously simple,” says David Baum, who first began thinking about an alternate theory to explain the rise of the eukaryotic cell as an Oxford University undergraduate 30 years ago. “It is a radical rethinking, taking what we thought we knew (about the cell) and turning it inside-out.”
By the end of yesterday’s two hour shoot the muscle weakness I suffer from was manifesting clearly. In my face, in my feet that would not pick up from the floor, in my arms that shook as if 50lb weights were hanging from my wrists. I know I ‘overdid’ it when muscle weakness persists into the next day, as does the unignorable pain that indicates cellular dysfunction. Today I can barely move from where I sit to the bathroom when I need to go. I cannot sit upright without total support of my body, my limbs and my head. I’m unable to separate my arms or hands from my body as I type this; only my fingers themselves are mobile. The searing burn in my upper arms and hands as I haltingly and weakly stab across this tablet’s touch screen keyboard is deemed 'exercise intolerance’ in medical terms. I dislike this term and find it misleading. Most people would describe exercise as a workout, or at the very least a good paced walk for a few miles. But, as with many words, what have one meaning in common lexicon will have another entirely in medicine. 'Exercise intolerance’ is a broad term with much variance in application among disease processes. For me, it relates to the muscular and cellular dysfunction I experience.
Today, just 2-3 chews on soft bread or a hand to my neck to scratch elicits a lactate burn from the pits of hell in the deepest depths of the muscles that are trying to activate. Many will be familiar with a mild form of this burn: usually as a result from running too hard, too long, or really, too much of any intense exercise in too short a period of time. It is, after all, a natural process. Some even pride themselves on this burn; it’s an indication for them that they are working hard. Lactic acid is a byproduct resulting from mitochondrial cells (energy production cells) using alternate forms of fuel when the correct sources are depleted. It is backup processing. This waste product causes pain, but in nearly all human beings this lactic burn will resolve within a couple of minutes to an hour once the exercise is stopped. (Other forms of muscle pain are different and likely a result of small tears, so take longer to resolve).
As long as I’m able to remember I’ve experienced lactate burn from as little as good paced walking, any amount of running, or even any kind of yoga or other mild activity. Now, as my conditions have progressed, the fiery pain manifests from even the simplest of daily activities; brushing my teeth, cooking, walking even 100m, propelling my wheelchair. It can last for days if I don’t get the correct nutrition, hydration, have trouble getting enough oxygen, don’t sleep enough or deplete my energy stores too rapidly or for too long a time. This is the price I pay every day now. Related, but different is the muscle weakness; the only outwardly visible sign that anything is malfunctioning.
I’m utterly exhausted writing this. I have to rest, but I want to thank you all for the supportive comments, the messages, the love. I have a hard time replying consistently for obvious reasons, but I read everything and I thank you. For watching, for reading, for learning, for your support.
