Tag Archives: Neuroscience

Two proteins work together to help cells eliminate trash and Parkinson’s may result when they don’t

Two proteins that share the ability to help cells deal with their trash appear to need each other to do their jobs and when they don’t connect, it appears to contribute to development of Parkinson’s disease, scientists report.

Much like a community’s network for garbage handling, cells also have garbage sites called lysosomes, where proteins, which are functioning badly because of age or other reasons, go for degradation and potential recycling, said Dr. Wen-Cheng Xiong, developmental neurobiologist and Weiss Research Professor at the Medical College of Georgia at Georgia Regents University.

Inside lysosomes, other proteins, called proteases, help cut up proteins that can no longer do their job and enable salvaging of things like precious amino acids. It’s a normal cell degradation process called autophagy that actually helps cells survive and is particularly important in cells such as neurons, which regenerate extremely slowly, said Xiong, corresponding author of the study in The Journal of Neuroscience.

Key to the process – and as scientists have shown, to each other – are two more proteins, VPS35 and Lamp2a. VPS35 is essential for retrieving membrane proteins vital to cell function. Levels naturally decrease with age, and mutations in the VPS35 gene have been found in patients with a rare form of Parkinson’s. VPS35 also is a critical part of a protein complex called a retromer, which has a major role in recycling inside cells. Lamp2a enables unfit proteins to be chewed up and degraded inside lysosomes.

If the two sound like a natural couple, scientists now have more evidence that they are. They have shown that without VPS35 to retrieve Lamp2a from the trash site for reuse, Lamp2a, or lysosomal-associated membrane protein 2, will be degraded and its vital function lost.

When the scientists generated VPS35-deficient mice, the mice exhibited Parkinson’s-like deficits, including impaired motor control. When they looked further, they found the lysosomes inside dopamine neurons, which are targets in Parkinson’s, didn’t function properly in the mice. In fact, without VPS35, the degradation of Lamp2a itself is accelerated. Consequently, yet another protein, alpha-synuclein, which is normally destroyed by Lamp2a, is increased. Alpha-synuclein is a major component of abnormal protein clumps, called Lewy bodies, found in the brains of patients with Parkinson’s.

“If alpha-synuclein is not degraded, it just accumulates. If VPS35 function is normal, we won’t see its accumulation,” Xiong said.

Conversely, when MCG scientists increased expression of Lamp2a in the dopamine neurons of the VPS35-deficient mice, alpha-synuclein levels were reduced, a finding that further supports the linkage of the three proteins in the essential ability of the neurons to deal with undesirables in their lysosomes.

Without lamp2a, dopamine neurons essentially start producing more garbage rather than eliminating it. Recycling of valuables such as amino acids basically stops, and alpha-synuclein is free to roam to other places in the cell or other brain regions where it can damage still viable proteins.

The bottom line is dopamine neurons are lost instead of preserved. Brain scans document the empty spaces where neurons used to be in patients with neurodegenerative diseases such as Parkinson’s and Alzheimer’s. One of the many problems with treatment of these diseases is that by the time the empty spaces and sometimes the associated symptoms are apparent, much damage has occurred, Xiong said.

Putting these pieces together provides several new, early targets for disease intervention. “Everything is linked,” Xiong said.

Dopamine is a brain chemical with many roles, including motor control, and patients with Parkinson’s have a loss of the neurons that secrete this neurotransmitter. At least in mice, VPS35 is naturally expressed in dopamine neurons in areas of the brain affected by Parkinson’s.

Xiong and her colleagues reported in 2011 that reduced expression of VPS35 enables activity of the dormant-in-healthy-adults protein BACE1 to increase along with accumulation of the brain plaque that is a hallmark of Alzheimer’s. Xiong said then that impaired VPS35 function likely also was a factor in Parkinson’s.

In a definite vicious circle, trash starts overwhelming the brain cell’s natural garbage disposal system. Proteins start getting misfolded and dysfunctional, potentially destructive proteins such as BACE1 and Lamp2a end up in the wrong place and get activated/inactivated, while good proteins get chopped up and/or bad proteins accumulate.

Parkinson’s disease is characterized by uncontrolled shaking, an unstable gait and cognitive loss. The research was funded by the National Institutes of Health and the Department of Veterans Affairs. Postdoctoral Fellow Dr. Fulei Tang is the study’s first author.

Estrogen receptor expression may help explain why more males have autism

AUGUSTA, Ga. – The same sex hormone that helps protect females from stroke may also reduce their risk of autism, scientists say.

In the first look at a potential role of the female sex hormone in autism, researchers at the Medical College of Georgia at Georgia Regents University have found expression of estrogen receptor beta – which enables estrogen’s potent brain protection – is significantly decreased in autistic brains. The receptor also plays a role in locomotion as well as behavior, including anxiety, depression, memory, and learning.

“If you ask any psychiatrist seeing patients with autistic behavior their most striking observation from the clinic, they will say there are more males compared to females,” said Dr. Anilkumar Pillai, MCG neuroscientist and corresponding author of the study in Molecular Autism.

Estrogen is known to help protect premenopausal women from maladies such as stroke and impaired cognition. Exposure to high levels of the male hormone testosterone during early development has been linked to autism, which is five times more common in males than females.

The new findings of reduced expression of estrogen receptor beta as well as that of an enzyme that converts testosterone to estrogen could help explain the high testosterone levels in autistic individuals and higher autism rates in males, Pillai said.

It was the 5-to-1 male-to-female ratio along with the testosterone hypothesis that led Pillai and his colleagues to pursue whether estrogen might help explain the significant gender disparity and possibly point toward a new treatment.

“The testosterone hypothesis is already there, but nobody had investigated whether it had anything to do with the female hormone in the brain,” Pillai said. “Estrogen is known to be neuroprotective, but nobody has looked at whether its function is impaired in the brain of individuals with autism. We found that the children with autism didn’t have sufficient estrogen receptor beta expression to mediate the protective benefits of estrogen.”

Comparing the brains of 13 children with and 13 children without autism spectrum disorder, the researchers found a 35 percent decrease in estrogen receptor beta expression as well as a 38 percent reduction in the amount of aromatase, the enzyme that converts testosterone to estrogen.

Levels of estrogen receptor beta proteins, the active molecules that result from gene expression and enable functions like brain protection, were similarly low. There was no discernable change in expression levels of estrogen receptor alpha, which mediates sexual behavior.

The study focused on the brain’s prefrontal cortex, which is involved in social behavior and cognition. Brain tissue from both autistic and healthy subjects was obtained from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland. The children died at an average age of 11 from drowning, other accidents, or suicide. All the brain tissue was from male children except for one control.

While much work remains, estrogen receptor beta agonists, which are already known to improve brain plasticity and memory in animals, might one day help reverse autism’s behavioral deficits, such as reclusiveness and repetitive behavior, Pillai said.

The scientists already are moving to animal studies to see what happens when they reduce estrogen receptor beta expression in mice. They also plan to give an estrogen receptor beta agonist – which should increase receptor function – to a mouse with generalized inflammation and signs of autism to see if it mitigates those signs. Inflammation is a factor in many diseases of the brain and body, and estrogen receptor beta agonists already are in clinical trials for schizophrenia

Larger, follow-up studies should also include comparing expression of testosterone receptor levels in healthy and autistic children, Pillai said. MCG scientists also want to know more about why the reduced beta receptor expression occurs.

Studies published in the journal Molecular Psychiatry earlier this year by scientists at the University of Cambridge and Denmark’s Statens Serum Institute showed that male children who develop autism were exposed to higher levels of steroid hormones, including testosterone and progesterone, during development than their healthy peers.

The incidence of autism has increased about 30 percent in the past two years in the United States, to the current rate of about 1 in 68 children, according to the Centers for Disease Control and Prevention. Most children are diagnosed at about age 4, although the disorder can be diagnosed by about age 2, according to the CDC. Diagnosis is made through extensive behavioral and psychological testing.

GRU graduate student Amanda Crider is first author on the study.

Virus, zebrafish enable scientists to map the living brain

AUGUSTA, Ga.  – A virus and a zebrafish are helping scientists map the living brain.

“You can kinda draw a diagram and see how cells within it are connected in a functioning brain,” said Dr. Albert Pan, neuroscientist at the Medical College of Georgia at Georgia Regents University. “This will help us see how wiring is laid and how it functions.”

Miswiring is believed to cause conditions such as mental retardation, autism, and schizophrenia. In autism, as an example, there may be too many connections in some brain areas and too few in others.

“We want everything to happen well in the embryo where a lot of this dividing and migrating and connecting is taking place,” Pan said. He recently received a $1.9 million grant from the National Eye Institute to develop a virus-based toolkit that will help scientists understand normal connectivity and, ultimately, what goes wrong in disease.

His model organism is the zebrafish and his model system visual function. While the tiny zebrafish may seem an odd choice, the transparent vertebrate is actually a great model, Pan said. The human brain has 70 billion cells compared to 100,000 in the zebrafish, but the brains have the same basic structure. The fact that the fish develops rapidly and transparently are two other huge pluses, he said.

Zebrafish start out as an external egg in a transparent shell, complete embryonic development in two days, and are full-grown fish by three months. By day 10, Pan equates them to young children who can readily manage most common, important behaviors, such as learning, despite the fact that their brains are still developing.

“It fits the timeframe of a scientist. In very small fish, you can look at very interesting behaviors in a vertebrate brain,” said Pan, who is the first to try virus-based brain mapping in zebrafish. Previous efforts to map neural circuits mostly have been done in mice.

“The unique thing about using this fish is that we can actually look at the neuronal activity while we are tracing, we can try different behavior tasks and see which cells are active, which cells are connected, and we can use different techniques to destroy different neurons and see how it affects behavior.”

Pan’s use of a mutant, super albino that lacks pigment further enhances his ability to keep his eye on functioning cells.

The fish are also transgenic so firing cells naturally light up, but visualizing the nanometer-scale synapses with a light microscope as they form is another matter. “If a cell fires, we can see kind of a spike of light coming out of those cells. So you can see the firing pattern of these cells. But you don’t know which cells are connected to each other, so it’s difficult to make sense of how the brain is transferring information from one part to another and how this information is processed,” he said.

That’s where a virus can help “do the heavy lifting.” The vesicular stomatitis virus, which is in the same family as rabies but doesn’t infect humans, has the uncanny propensity to travel across synapses. So he is using VSV, armed with a fluorescent agent, to fill in the important blanks of when and how cells connect. “What this grant is about is developing a new tool where you can see these connections and how one cell is connected to another cell,” Pan said.

The brain’s basic organizational structure is neural circuits, groupings of brain cells for a common purpose like sight or smell or movement. “If you think of it like a computer, it’s different software that does different things,” Pan said. Different circuits also integrate so the brain works as a cohesive unit.

The transparency of the zebrafish is enabling him to watch the visual circuit from essentially the beginning, when neural progenitor cells, destined to be neurons, first appear around the donut hole of the neural tube, a hollow tube that forms the brain and spinal cord.

Neural progenitor cells split, then migrate out, with gradients and the distinctive smell of different proteins guiding them – if all goes well – to their rightful place in the developing brain.  Pan uses the analogy of pouring cream in coffee and its natural motion away from that point.

“Cells can sense the proteins and know where they are within the body plan. They know what type cell they should be and where they should migrate,” Pan said.

Once in place, neurons wire together and connect by forming synapses that enable communication. Synapses can be short lived, to help you remember how much apples cost until you get out of the grocery store, or long-term, so you always remember your mother’s voice and face.

He notes that the additional information he learns about the visual neural circuit will lead to better understanding of this important neural circuit as well as related behaviors – like how the eyes naturally follow a moving car – in addition to providing a model for studying other circuits.

“A lot of what we already understand about the brain comes from vision research,” said Pan. His studies will include eliminating some cells, seeing if the zebrafish, also known for its regenerative ability, will regrow the cells, and if those new cells will integrate into the existing circuitry.

MCG establishes Department of Neuroscience and Regenerative Medicine

LinMeiwebfrontA Department of Neuroscience and Regenerative Medicine that further strengthens research and educational endeavors in neurological and psychiatric disease has been established at the Medical College of Georgia at Georgia Regents University.

Dr. Lin Mei, a neuroscientist and expert in brain cell communication who has directed MCG’s Institute of Molecular Medicine and Genetics for six years, is the inaugural Chairman of the department that also will pursue the restorative potential of stem cells.

“Neurological and psychiatric disease, from stroke, to autism, to schizophrenia and Alzheimer’s, have significant, lasting and frequently devastating effects on the citizens of our state and nation,” said Dr. Peter F. Buckley, MCG Dean. “Under the leadership of Dr. Mei, this new department will further strengthen our already significant contributions in this field.”

Innovative, translational research as well as medical and graduate student education and postdoctoral mentoring will be a department focus, Mei said. Goals include expanding teaching responsibilities to include undergraduates at GRU’s Summerville Campus and pursuing federal support for a graduate-level neuroscience training program. Currently about 60 postdoctoral fellows and students are working with the department’s initial 26 faculty members.

Dr. Carlos M. Isales, who has served as Chief of the Institute’s Program in Regenerative Medicine, is Vice Chairman of Clinical Affairs of the new department. Drs. Darrell Brann, Associate Director of the Institute of Molecular Medicine and Genetics, is the Vice Chairman of Academic Affairs.

“These terrific leaders will work closely and collaboratively with Drs. David Hess and Cargill Alleyne in our Departments of Neurology and Neurosurgery as well as Dr. Joe Tsien in the Brain and Behavior Discovery Institute and many others across our campus and the world to advance our understanding and treatment of the brain,” Buckley said. “Collectively, these strategic realignments enhance our focus on neuroscience across clinical, basic science, and translational realms.”
“We believe this is the right time to form a department with a focus on research and educational initiatives in the brain as well as regenerative medicine, which uses human cells and tissue to repair our bodies,” Mei said. He noted President Barack Obama’s 2013 announcement of the National Institutes of Health BRAIN Initiative to revolutionize the understanding of the human brain by accelerating the development and application of new technologies, which provide a more dynamic picture of the functioning brain.

Mei, a Georgia Research Alliance Eminent Scholar in Neuroscience, is Associate Editor of the Journal of Neuroscience, Section Editor of Molecular Brain, and a member of the Editorial Board of NeuroSignals and Neuroscience Bulletin. He is a member of the International Advisory Board of the International Symposium on Cholinergic Mechanisms and chaired the 2012 Gordon Research Conference on Molecular and Cellular Neurobiology.

He received the 2008 Mathilde Solowey Lecture Award in the Neurosciences from the NIH’s Foundation for Advanced Education in Sciences and was a 2008 Distinguished Investigator of the National Alliance for Research on Schizophrenia and Depression. He was elected a Fellow of the American Association for the Advancement of Science in late 2013.

ALS Walk slated for Sept. 28

AUGUSTA, Ga. – Patients, families, employees and friends will Beat Feet for ALS at 8 a.m. Saturday, Sept. 28 at Augusta’s Riverwalk in an effort to raise money for the Georgia Regents ALS Clinic.

ALS, or amyotrophic lateral sclerosis, is more commonly known as Lou Gehrig’s Disease, named for the first baseman and power hitter for the New York Yankees. Gehrig was stricken with the neurodegenerative disease that causes muscular atrophy and forced into retirement at age 36. It claimed his life two years later.

Nearly 6,000 people in the United States are diagnosed with ALS each year, and the life expectancy is just two to five years. But effects of the disease vary, and many people can live with quality for five years and more with the help of nationally accredited clinics like the one at Georgia Regents.

Formed in 2004 through a partnership between the Georgia Regents Neuroscience Center and the ALS Association of Georgia, the clinic serves about 100 ALS patients across the Southeast.  Because ALS patients lose the use of their muscles, it becomes difficult for them to make multiple trips for several appointments, so the clinic features a comprehensive, multidisciplinary and coordinated approach to patient care.  Patients can see their neurologists and nurses as well as physical, occupational and speech therapists, social workers, dietitians and respiratory therapists on the same day.

The clinical team sees patients on the second Friday of each month in Augusta and the last Friday of each month at a satellite clinic in Macon in order to assess disease progression, functional status, family concerns, and equipment and referral needs. Family and caregiver training are incorporated into the time spent with each patient. In addition, an ALS Support Group meeting is part of the monthly clinic experience.

“Insurance doesn’t always pay for multiple visits and additional services at the clinic, but studies have shown that being seen in a multidisciplinary clinic improves the longevity of patients – their health and quality of life,” said Dr. Michael H. Rivner, Medical Director of the ALS Clinic and Professor of Neurology for the Medical College of Georgia at Georgia Regents University. “We hope to raise additional funds to meet our patients’ needs through this walk.”

To register for the walk or make a donation, visit walk.ALSGRU.com or contact Brandy Quarles at 706-721-2681 or bquarles@gru.edu. The walk is sponsored by Accredo, Allergan and Integrity Medical.

Georgia Regents Medical Center becomes Georgia’s first Advanced Comprehensive Stroke Center

Neuroscience Nurse Berkley Shields (left) and Neurointensivist Dr. Subhashini Ramesh talk with recovering stroke patient Alice Lewis, 46, at Georgia Regents Medical Center. The medical center is the only hospital in Georgia to be named an Advanced Comprehensive Stroke Center by the Joint Commission for complex stroke care.
Neuroscience Nurse Berkley Shields (left) and Neurointensivist Dr. Subhashini Ramesh talk with recovering stroke patient Alice Lewis, 46, at Georgia Regents Medical Center. The medical center is the only hospital in Georgia to be named an Advanced Comprehensive Stroke Center by the Joint Commission for complex stroke care.

AUGUSTA, Ga. – The Joint Commission on the Accreditation of Health Care Organizations has designated Georgia Regents Medical Center as an Advanced Comprehensive Stroke Center, making it the only hospital in Georgia and one of less than 20 hospitals nationwide to achieve this designation.

“This means we provide high-level care for patients with the most severe and challenging types of strokes and cerebrovascular disease, and we help set the national standards in highly-specialized stroke care,” said David S. Hefner, CEO of the medical center. “It’s not any one thing that we do here; it’s a myriad of best-practices performed by specially-trained staff from a variety of health care disciplines, all working together to provide better outcomes for our stroke patients.”

A stroke or brain attack occurs when a blood vessel that carries oxygen and nutrients to the brain is either blocked by a clot or ruptures. When that happens, part of the brain cannot get the blood it needs, so brain cells die. Stroke is a leading cause of death and serious long-term disability in the United States, and especially Georgia, because it is located in the stroke belt.

During a rigorous two-day onsite review, Joint Commission experts examined the medical center’s compliance with Comprehensive Stroke Center standards and requirements, including 24/7 availability of specialized treatments, staff with the unique education and competencies to care for complex stroke patients and advanced imaging capabilities.

Last year, Georgia Regents Medical Center opened one of two new interventional radiology suites, becoming the first hospital in Georgia equipped with VasoCT imaging. This technology produces clear, three-dimensional pictures of the arteries and veins in the brain and neck that allow the hospital’s neurosurgery team to better pinpoint and open blockages. In addition, having two interventional suites means the hospital may treat more than one complex patient at a time, another Comprehensive Stroke Center requirement.

Surveyors also looked at post-hospital care coordination for patients and patient-centered stroke research efforts. Physician scientists at Georgia Regents University are currently researching the ways in which leg compressions, stem cell therapy and insulin administration methods affect stroke recovery.

Comprehensive Stroke Center Certification was developed in collaboration with the Brain Attack Coalition and the American Heart Association/American Stroke Association. The AHA/ASA awarded Georgia Regents Medical Center with its second consecutive Get With The Guidelines® Stroke Gold Plus Quality Achievement Award in 2012, and the hospital was named to the AHA/ASA Target: Stroke Honor Roll for excellence in emergency stroke care in December.

Georgia Regents Medical Center extends quality stroke care to rural patients throughout the region through REACH Health, Inc., a telemedicine program pioneered in 2003 at GRU’s Medical College of Georgia. This hub-and-spoke network allows stroke specialists at Georgia Regents Medical Center (the hub) to diagnose and treat stroke patients remotely at more than a dozen rural and a few larger community hospitals in Georgia and to transport those in need of surgery or more specialized neurointensive critical care to GRMC.

Those spoke hospitals are Burke Medical Center, Coliseum Medical Centers, Elbert Memorial Hospital, Emanuel Medical Center, Fairview Park Hospital, Doctors Hospital, Jefferson Hospital, Jenkins County Hospital, McDuffie Regional Medical Center, Morgan Memorial Hospital, St. Mary’s Hospital, St. Mary’s Good Samaritan Hospital, Tift Regional Medical Center, Washington County Regional Medical Center, West Georgia Hospital and Wills Memorial Hospital.

Georgia Regents Medical Center also collaborates with neighboring emergency medical services or EMS teams by providing pre-hospital and interventional stroke care education, covering everything from field recognition of stroke to proper patient transport.