Researchers Recreate Pain-Sensing Neurons

Researchers at the Harvard Stem Cell Institute and the Stem Cell and Regenerative Biology Department have successfully developed pain-sensing neurons from mouse and human skin cells, according to a report published in Nature Neuroscience in late November.

The study specifically aimed to simulate primary afferent nociceptors, very specialized pain-sensing neurons.

According to head researcher Clifford J. Woolf, a professor of Neurology and Neurobiology at theMedical School, the findings may lead to development of more effective pain medications, better methods to evaluate who is at risk for developing chronic pain, and ways to combat pain complications resulting from cancer chemotherapy.

What weve been able to do with stem cell technology for the first time is recreate some of the key elements of the nervous system by taking one cell and turning it into a particular other cell, Woolf said. This enables us for the first time to really dissect how human neurons function in the nervous system.

For Woolf, the study is a culmination of many years of research, previously done only in mouse cells.

The fact that we can even create these cells with a human gives us the opportunity to study the mechanisms of the way human nervous systems work that havent been possible before, Woolf said.

Tony L. Yaksh, co-director of the Pain and Symptom Management Core of the University of California at San Diegos Regional Cancer Center, emphasized the studys role in raising new questions for further research.

I think this is highly innovative and an extremely well-done paper, Yaksh said. Id say this represents a very concerted, well-organized group effort to define this very critical issue. It leaves you with more questions than before you read the paper, but it starts the ball rolling in a very exciting way.

Yaksh also highlighted the importance of the study in streamlining gene-specific treatment.

The significance is [that] this allows us to define a mechanism that may be relevant to pain transmission in humans without having to euthanize a human being, Yaksh said.

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Researchers Recreate Pain-Sensing Neurons

Fear of unknown barrier to iPS cures, expert says

Masayo Takahashi, who led the worlds first operation to implant induced pluripotent stem (iPS) cells into a human body, says greater Japanese understanding of the risks and benefits of new medical procedures is key to achieving her goal of standardizing the procedure one day.

About two months after her team successfully transplanted retinal cells grown from iPS cells into a woman in her 70s with age-related macular degeneration, Takahashi, an ophthalmologist at the Riken Center for Developmental Biology in Kobe, said she wanted to make the treatment available and affordable in about 10 years.

My goal is to make the treatment a standard one, Takahashi said Wednesday at the Foreign Correspondents Club of Japan in Tokyo, adding that the pioneering operation in September was just a start.

The operation was primarily aimed at checking for any medical problems that might arise, including the possibility of cancer, after iPS-derived retinal cells were transplanted to the patient, whose form of the disease could lead to loss of vision.

It is expected to take around a year to assess the safety and side effects of the transplant operation.

The most difficult part of the surgery was removal of damaged tissue, Takahashi said. So we were very excited when the damaged tissue was removed safely.

The surgery, performed by a team of researchers at the Riken institute and the Institute of Biomedical Research and Innovation Hospital, was the first in which iPS-derived cells were introduced into a human body.

Developed by Nobel Prize-winning Kyoto University professor Shinya Yamanaka, iPS cells are a versatile type of stem cell that can grow into various types of human body tissue.

However, a potential obstacle to spreading the treatment is reluctance among Japanese to take risks when they encounter something new, including medical treatments, according to Takahashi.

In Japan, people dont accept risks at all, she said, adding it is necessary to accept a certain level of risk when receiving advanced medicine and it is important to understand the balance between risks and benefits.

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Fear of unknown barrier to iPS cures, expert says

Cardiac Stem Cells (CSCs) | University of Maryland Medical …

For immediate release: September 10, 2012

Baltimore, MD --Researchers at the University of Maryland School of Medicine, who are exploring novel ways to treat serious heart problems in children, have conducted the first direct comparison of the regenerative abilities of neonatal and adult-derived human cardiac stem cells. Among their findings: cardiac stem cells (CSCs) from newborns have a three-fold ability to restore heart function to nearly normal levels compared with adult CSCs. Further, in animal models of heart attack, hearts treated with neonatal stem cells pumped stronger than those given adult cells. The study is published in the September 11, 2012, issue of Circulation.

The surprising finding is that the cells from neonates are extremely regenerative and perform better than adult stem cells, says the study's senor author, Sunjay Kaushal, M.D., Ph.D., associate professor of surgery at the University of Maryland School of Medicine and director, pediatric cardiac surgery at the University of Maryland Medical Center. We are extremely excited and hopeful that this new cell-based therapy can play an important role in the treatment of children with congenital heart disease, many of whom don't have other options.

Dr. Kaushal envisions cellular therapy as either a stand-alone therapy for children with heart failure or an adjunct to medical and surgical treatments. While surgery can provide structural relief for some patients with congenital heart disease and medicine can boost heart function up to two percent, he says cellular therapy may improve heart function even more dramatically. We're looking at this type of therapy to improve heart function in children by 10, 12, or 15 percent. This will be a quantum leap in heart function improvement.

Heart failure in children, as in adults, has been on the rise in the past decade and the prognosis for patients hospitalized with heart failure remains poor. In contrast to adults, Dr. Kaushal says heart failure in children is typically the result of a constellation of problems: reduced cardiac blood flow; weakening and enlargement of the heart; and various congenital malformations. Recent research has shown that several types of cardiac stem cells can help the heart repair itself, essentially reversing the theory that a broken heart cannot be mended.

Stem cells are unspecialized cells that can become tissue- or organ-specific cells with a particular function. In a process called differentiation, cardiac stem cells may develop into rhythmically contracting muscle cells, smooth muscle cells or endothelial cells. Stem cells in the heart may also secrete growth factors conducive to forming heart muscle and keeping the muscle from dying.

To conduct the study, researchers obtained a small amount of heart tissue during normal cardiac surgery from 43 neonates and 13 adults. The cells were expanded in a growth medium yielding millions of cells. The researchers developed a consistent way to isolate and grow neonatal stem cells from as little as 20 milligrams of heart tissue. Adult and neonate stem cell activity was observed both in the laboratory and in animal models. In addition, the animal models were compared to controls that were not given the stem cells.

Dr. Kaushal says it is not clear why the neonatal stem cells performed so well. One explanation hinges on sheer numbers: there are many more stem cells in a baby's heart than in the adult heart. Another explanation: neonate-derived cells release more growth factors that trigger blood vessel development and/or preservation than adult cells.

This research provides an important link in our quest to understand how stem cells function and how they can best be applied to cure disease and correct medical deficiencies, says E. Albert Reece, M.D., Ph.D., M.B.A., vice president for medical affairs, University of Maryland; the John Z. and Akiko K. Bowers Distinguished Professor; and dean, University of Maryland School of Medicine. Sometimes simple science is the best science. In this case, a basic, comparative study has revealed in stark terms the powerful regenerative qualities of neonatal cardiac stem cells, heretofore unknown.

Insights gained through this research may provide new treatment options for a life-threatening congenital heart syndrome called hypoplastic left heart syndrome (HLHS). Dr. Kaushal and his team will soon begin the first clinical trial in the United States to determine whether the damage to hearts of babies with HLHS can be reversed with stem cell therapy. HLHS limits the heart's ability to pump blood from the left side of the heart to the body. Current treatment options include either a heart transplant or a series of reconstructive surgical procedures. Nevertheless, only 50-60 percent of children who have had those procedures survive to age five.

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November Tip Sheet from Cedars-Sinai Medical Center

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Newswise Following is the November 2014 tip sheet of story ideas from Cedars-Sinai Medical Center. To arrange interviews, please contact the individual listed.

Familys Battle With Cancer Draws Nurse Into Run for Her Brenda Durand, RN, followed in the footsteps of her mother, Bonnie, and became a nurse. But the two women had more in common than their careers. In 2004, Bonnie was diagnosed with stage 3 ovarian cancer. Two years later, Brendas sister learned she had breast cancer, prompting the mother and her two daughters to undergo genetic testing. The results came back: All three women carried the BRCA 1 mutation, putting them at greater risk for breast and ovarian cancer. For the next six years, Brenda and her mom worked to raise funds for ovarian cancer research, with Brenda participating in Cedars-Sinais annual Run for Her 5K Run and Friendship Walk. In 2012, Bonnie lost her life to ovarian cancer. But the loss of her mother has strengthened Brendas resolve to fight harder against ovarian cancer, and on Nov. 9, she participated in the 10th annual Run for Her. She is available for interviews. CONTACT: Cara Martinez, 310-423-7798; Email cara.martinez@cshs.org

Lou Gehrigs Disease Study: Renewing Brains Aging Support Cells May Help Neurons Survive Lou Gehrigs disease, also known as amyotrophic lateral sclerosis, or ALS, attacks muscle-controlling nerve cells motor neurons in the brain, brainstem and spinal cord, leading to progressive weakness and eventual paralysis of muscles throughout the body. Patients typically survive only three to five years after diagnosis. Now, with publication of a study by investigators at the Cedars-Sinai Board of Governors Regenerative Medicine Institute, ALS researchers know the effects of the attack are worsened, at least in part, by the aging and failure of support cells called astrocytes, which normally provide nutrients, housekeeping, structure and other forms of assistance for neurons. CONTACT: Sandy Van, 808-526-1708; Email sandy@prpacific.com

Cardiac Stem Cell Therapy May Heal Heart Damage Caused by Duchenne Muscular Dystrophy Researchers at the Cedars-Sinai Heart Institute have found that injections of cardiac stem cells might help reverse heart damage caused by Duchenne muscular dystrophy, potentially resulting in a longer life expectancy for patients with the chronic muscle-wasting disease. CONTACT: Sally Stewart, 310-248-6566; Email sally.stewart@cshs.org

Cedars-Sinai Study of Lou Gehrigs Disease Shifts Origin Focus to Brains Motor Neurons Lou Gehrigs disease, also known as amyotrophic lateral sclerosis, or ALS, might damage muscle-controlling nerve cells in the brain earlier in the disease process than previously known, according to research from the Cedars-Sinai Board of Governors Regenerative Medicine Institute. The findings could shift researchers attention from the spinal cord to the brains motor cortex as the diseases initial point of dysfunction. CONTACT: Sandy Van, 808-526-1708; Email sandy@prpacific.com

New Alzheimers Program to Focus on Prevention, Intervention, Research and Support Seeking to stem the rapid increase of Alzheimers disease, Cedars-Sinai has launched a new Alzheimers Prevention Program to help identify patients at risk of developing the neurological disorder and to reduce the impact on those diagnosed with the slow-moving condition. The program represents a concerted effort by clinicians, researchers, patients, families, caregivers and community agencies to address an approaching tsunami of Alzheimers care. Medical authorities expect the number of cases nationally to triple by 2050, inundating the healthcare system with patients and costing more than $1 trillion. CONTACT: Sandy Van, 808-526-1708; Email sandy@prpacific.com

Sister to Sister, Nations First Organization Dedicated to Womens Heart Health, Donates Educational Content, Intellectual Property to Cedars-Sinai Heart Institute

After 15 years of educating women about heart disease and providing more than 100,000 free cardiovascular screenings, Sister to Sister: The Womens Heart Health Foundation founded by Irene Pollin, MSW, announced today that the organization will cease operations on Dec. 31. Pollin also announced that the pioneering organization is donating its educational content and intellectual property to the Barbra Streisand Womens Heart Center in the Cedars-Sinai Heart Institute. CONTACT: Sally Stewart, 310-248-6566; Email sally.stewart@cshs.org

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UCLA Researchers Unlock Protein Key to Harnessing Regenerative Power of Blood Stem Cells

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Newswise In a study led by Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research member, Dr. John Chute, UCLA scientists have for the first time identified a unique protein that plays a key role in regulating blood stem cell replication in humans.

This discovery lays the groundwork for a better understanding of how this protein controls blood stem cell growth and regeneration, and could lead to the development of more effective therapies for a wide range of blood diseases and cancers.

The study was published online November 21, 2014 ahead of print in the Journal of Clinical Investigation.

Hematopoietic stem cells (HSCs) are the blood-forming cells that have the remarkable capacity to both self-renew and give rise to all of the differentiated cells (fully developed cells) of the blood system. HSC transplantation provides curative therapy for thousands of patients annually. However, little is known about the process through which transplanted HSCs replicate following their arrival in human bone marrow. In this study, the authors showed that a cell surface protein called protein tyrosine phosphatase-sigma (PTP-sigma) regulates the critical process called engraftment, meaning how HSCs start to grow and make health blood cells after transplantation.

Mamle Quarmyne, a graduate student the lab of Dr. Chute and first author of the study, demonstrated that PTP-sigma is produced (expressed) on a high percentage of mouse and human HSCs. She showed further that genetic deletion of PTP-sigma in mice markedly increased the ability of HSCs to engraft in transplanted mice.

In a complementary study, she demonstrated that selection of human blood HSCs which did not express PTP-sigma led to a 15-fold increase in HSC engraftment in transplanted immune-deficient mice. Taken together, these studies showed that PTP-sigma suppresses normal HSC engraftment capacity and targeted blockade of PTP-sigma can substantially improve mouse and human HSC engraftment after transplantation.

Chute and colleagues showed further that PTP-sigma regulates HSC function by suppressing a protein, RAC1, which is known to promote HSC engraftment after transplantation.

These findings have tremendous therapeutic potential since we have identified a new receptor on HSCs, PTP-sigma, which can be specifically targeted as a means to potently increase the engraftment of transplanted HSCs in patients, said Chute, senior author of the study and UCLA Professor of Hematology/Oncology and Radiation Oncology. This approach can also potentially accelerate hematologic recovery in cancer patients receiving chemotherapy and/or radiation, which also suppress the blood and immune systems.

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UCLA Researchers Unlock Protein Key to Harnessing Regenerative Power of Blood Stem Cells

Establishment of induced pluripotent stem cells from Werner syndrome fibroblasts

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Associate Professor Akira Shimamoto and Professor Hidetoshi Tahara at the Graduate School of Biomedical & Health Science in Hiroshima University, Professor Koutaro Yokote at the Graduate School of Medicine in Chiba University, Visiting Professor Makoto Goto at the Medical Center East in Tokyo Women's Medical University, and collaborators including the staff at the Cancer Chemotherapy Center in the Japanese Foundation for Cancer Research, Tottori University, and Keio University established induced pluripotent stem (iPS) cells from the fibroblasts of Werner Syndrome patients.

These results were published in PLOS ONE in an article entitled "Reprogramming Suppresses Premature Senescence Phenotypes of Werner Syndrome Cells and Maintains Chromosomal Stability over Long-Term Culture."

Werner syndrome is characterized by the premature appearance of features associated with normal aging and cancer predisposition. This syndrome occurs frequently in Japan, affecting 1 in 20,000 to 1 in 40,000 people. The therapeutic methods for this disease are very limited and it is expected that iPS cells can be used for the development of innovative therapies.

Dr. Shimamoto and his collaborators analyzed patient-derived iPS cells and found that telomeric abnormalities in the fibroblasts of these patients, which were caused by the lack of WRN helicase encoded by the gene responsible for Werner syndrome, were recovered in the iPS cells generated from these patients. Furthermore, Dr. Shimamoto found that the expression levels of aging-related genes, including those encoding cell cycle inhibitors and inflammatory cytokines, in the patient-derived iPS cells were the same as those in normal iPS cells, even though the expression levels of these genes in the fibroblasts of the patients were higher than those in normal fibroblasts.

Dr. Shimamoto said, "So far, the use of patient cells was restricted to blood or dermal cells in basic research. The iPS cells that we have established will provide an opportunity for drug discovery for the treatment of Werner syndrome and also help with better understanding of the mechanism of this disease. In addition, the mutated WRN gene in patient-derived iPS cells can be corrected by genome editing. This advantage will be help in the development of new gene and cell therapies for Werner syndrome."

Explore further: Scientists find that SCNT derived cells and IPS cells are similar

Journal reference: PLoS ONE

Provided by Hiroshima University

A team led by New York Stem Cell Foundation (NYSCF) Research Institute scientists conducted a study comparing induced pluripotent stem (iPS) cells and embryonic stem cells created using somatic cell nuclear transfer (SCNT). ...

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Establishment of induced pluripotent stem cells from Werner syndrome fibroblasts

Beyond Batten Disease Foundation and the New York Stem Cell Foundation Chosen as a National Innovator by the Milken …

New York, New York (PRWEB) November 17, 2014

Beyond Batten Disease Foundation (BBDF) and the New York Stem Cell Foundation (NYSCF) have been selected as a national innovator by the Milken Institute and will present their breakthrough findings about juvenile Batten disease at the 6th annual Partnering for Cures, November 16-18 in New York City. The presentation will highlight the collaborative efforts of NYSCF, BBDF and Batten Disease Support and Research Association.

Craig and Charlotte Benson established Beyond Batten Disease Foundation in August 2008 after their then five-year-old daughter, Christiane, was diagnosed with juvenile Batten disease. Together with hundreds of families affected by Batten disease, and many more supporters who share their hope and resolve, they are working tirelessly to create a brighter future for Christiane, and all children with Batten disease.

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The Benson Family Story

Beyond Batten Disease and the New York Stem Cell Foundation hope to ramp up funding and partnerships to develop stem cell resources to investigate and explore new treatments and ultimately find a cure for juvenile Batten disease, a fatal illness-affecting children as they convene at the FasterCures, conference. The Washington, D.C.-based center of the Milken Institute will bring together nearly 1,000 medical research leaders, investors and decision-makers to forge the collaborations needed to speed and improve outcomes-driven R&D. NYSCF scientists have created the first iPS cells from a neurological disease and the first ever stem cell disease model from any disease. This discovery was named Time Magazine #1 breakthrough in 2008 because it was the first time anyone has made stem cells from a person with a disease and used them to produce the type of cell that degenerated in that patient. Again, in 2012 Time Magazine recognized the Beyond Batten Disease Foundations creation of a rate genetic disease test as a top ten medical breakthrough.

We know the genetic mutations associated with juvenile Batten disease. This partnership will result in stem cell models of juvenile Batten, giving researchers an unprecedented look at how the disease develops, speeding research towards a cure, said Susan L. Solomon, NYSCF Chief Executive Officer.

Working with NYSCF to generate functional neuronal subtypes from patients and families is a stellar example of one of our key strategies in the fight against juvenile Batten disease: creating resource technology with the potential to transform juvenile Batten disease research and accelerate our timeline to a cure, said Danielle M. Kerkovich, PhD, BBDF Principal Scientist.

Juvenile Batten disease begins in early childhood between the ages of five and ten. Initial symptoms typically begin with progressive vision loss, followed by personality changes, behavioral problems, and slowed learning. These symptoms are followed by a progressive loss of motor functions, eventually resulting in wheelchair use and premature death. Seizures and psychiatric symptoms can develop at any point in the disease.

Juvenile Batten disease is one disorder in a group of rare, fatal, inherited disorders known as Batten disease. Over 40 different errors (mutations) in the CLN3 segment of DNA (gene) have been attributed to juvenile Batten disease. The pathological hallmark of juvenile Batten is a buildup of lipopigment in the bodys tissues. It is not known why lipopigment accumulates or why brain and eventually, heart cells are selectively damaged. It is, however, clear that we need disease-specific tools that reflect human disease in order to figure this out and to build therapy.

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How adult fly testes keep from changing into ovaries

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New research in flies shows how cells in adult reproductive organs maintain their sexual identity. The study, publishing online on November 13 in the Cell Press journal Developmental Cell, also identified a mutation that can switch the cells' sexual identity. The findings could lead to new insights on how to alter cells for therapeutic purposes.

Sperm and eggs are made from germ cells, but instructions from their neighboring support cellscalled somatic cellsare also essential for their development. By studying the formation of sperm in fruit flies, which is remarkably similar to the process that occurs in people, investigators serendipitously found a mutation that gave testes a very unusual appearance. "Rather than becoming sperm, germ cells were stuck at an early stage, and they were surrounded by support cells that looked suspiciously like those belonging in an ovary," says senior author Dr. Erika Matunis of The Johns Hopkins School of Medicine. Her research team found that the mutation blocked the function of a specific gene in the stem cells that becomes support cells in the testis, causing the fruit flies to change from a male to a female identity.

The research is the first to show that adult stem cells actively maintain their sexual identity. The mutation the investigators found causes the stem cells in males to switch their sexual identities and start making support cells that belong in the ovary. This ultimately derails the production of sperm. "The molecules that govern this process are highly conserved, which suggests that similar mechanisms could operate in human testes," says Matunis.

The changes seen in this study are an example of transdifferentiation, or the conversion from one cell type to another. The topic is of considerable interest because promoting transdifferentiation in a directed manner may be useful for regenerating damaged organs or tissues. Doing so will require a thorough understanding of how cell fate conversions are regulated. "We are excited to have a powerful genetic system for studying transdifferentiation of stem cells at the mechanistic level," says Matunis. The research might also provide insights into how cells transform from a normal state to a cancerous one.

Explore further: Surprise: Lost stem cells naturally replaced by non-stem cells, fly research suggests

More information: Developmental Cell, Ma et al.: "The Jak-STAT target Chinmo prevents sex transformation of adult stem cells in the Drosophila testis niche" http://www.cell.com/developmental-cel 1534-5807(14)00628-5

Journal reference: Developmental Cell

Provided by Cell Press

Johns Hopkins researchers have discovered an unexpected phenomenon in the organs that produce sperm in fruit flies: When a certain kind of stem cell is killed off experimentally, another group of non-stem cells can come out ...

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How adult fly testes keep from changing into ovaries

Study Identifying Cell of Origin for Large, Disfiguring Nerve Tumors Lays Groundwork for Development of New Therapies

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Newswise DALLAS November 11, 2014 UTSouthwestern Medical Center researchers have determined the specific type of cell that gives rise to large, disfiguring tumors called plexiform neurofibromas, a finding that could lead to new therapies for preventing growth of these tumors.

This advance provides new insight into the steps that lead to tumor development and suggests ways to develop therapies to prevent neurofibroma formation where none exist today, said Dr. Lu Le, Assistant Professor of Dermatology at UTSouthwestern and senior author of the study, published online and in Cancer Cell.

Plexiform neurofibromas, which are complex tumors that form around nerves, occur in patients with a genetic disorder called neurofibromatosis type 1 (NF1), which affects 1 in 3,500 people. About 30 percent of NF1 patients develop this type of tumor, which is typically benign.

NF1 patients with plexiform neurofibromas, however, have a 10 percent lifetime risk of the tumors developing into malignant peripheral nerve sheath tumors (MPNSTs), a deadly, incurable type of soft-tissue cancer. In addition, due to their unusual capacity for growth, plexiform neurofibromas can be life-threatening by their physical impairment of vital organs or neural function.

While there are no currently approved therapies for either MPNSTs or plexiform neurofibromas, Dr. Le said determining the cell type and location from which these tumors originate is an important step toward discovering new drugs that inhibit tumor development.

If we can isolate and grow the cells of origin for neurofibromas, then we can reconstruct the biological steps that lead these original cells to tumor stage, said Dr. Le, a member of the Harold C. Simmons Cancer Center. Once we know the critical steps in the process, then we can design inhibitors to block each step in an effort to prevent or slow tumor formation.

Using a process called genetic labeling for cell fate tracing, researchers determined that plexiform neurofibromas originate from Schwann cell precursors in embryonic nerve roots.

This study addresses a fundamental question in the neurofibromatosis field, Dr. Le said. It points to the importance of stem cells and their immediate progenitors in the initiation of tumors, consistent with the notion that these neoplasms originate in a subset of primitive precursors and that most cells in an organ do not generate tumors.

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Study Identifying Cell of Origin for Large, Disfiguring Nerve Tumors Lays Groundwork for Development of New Therapies

Scientists create Parkinson's disease in a dish

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6-Nov-2014

Contact: David McKeon dmckeon@nyscf.org 212-365-7440 New York Stem Cell Foundation @nyscf

New York, NY (November 6, 2014) - A team of scientists led by The New York Stem Cell Foundation (NYSCF) Research Institute successfully created a human stem cell disease model of Parkinson's disease in a dish. Studying a pair of identical (monozygotic) twins, one affected and one unaffected with Parkinson's disease, another unrelated Parkinson's patient, and four healthy control subjects, the scientists were able to observe key features of the disease in the laboratory, specifically differences in the patients' neurons' ability to produce dopamine, the molecule that is deficient in Parkinson's disease. In addition, the scientists also identified a potential strategy for developing novel therapies for Parkinson's disease.

Attributed to a combination of genetic and nongenetic factors, Parkinson's disease has no completely effective therapy or cure. Parkinson's disease is moderately heritable, but the mechanisms of this inheritance are not well understood. While genetic forms of the disease exist, sporadic forms are far more common.

"The unique scenario of identical twins, one with this disease and one without, allowed our scientists an unprecedented look into the mechanisms of Parkinson's disease," said Susan L. Solomon, NYSCF Chief Executive Officer. "Advanced stem cell research techniques allow us to push the boundaries of science and see what actually goes wrong at the cellular level, step by step during the disease process."

DNA mutations resulting in the production of a specific enzyme called glucocerebrosidase (GBA) have been linked to a five-fold greater risk of developing Parkinson's disease; however, only 30% of individuals with this mutation have been shown to develop Parkinson's disease by the age of 80. This discordance suggests that multiple factors contribute to the development of Parkinson's disease, including both genetic and non-genetic factors. To date, there has been no appropriate model to identify and test multiple triggers leading to the onset of the disease.

In this study, published today in Cell Reports, a set of identical twins, both with a GBA mutation, provided a unique opportunity to evaluate and dissect the genetic and non-genetic contributions to the development of Parkinson's disease in one twin, and the lack of disease in the other. The scientists made induced pluripotent stem (iPS) cells from skin samples from both twins to generate a cellular model of Parkinson's in a dish, recapitulating key features of the disease, specifically the accumulation of -synuclein and dopamine deficiency.

Upon analyzing the cell models, the scientists found that the dopamine-producing neurons from both twins had reduced GBA enzymatic activity, elevated -synuclein protein levels, and a reduced capacity to synthesize and release dopamine. In comparison to his unaffected brother, the neurons generated from the affected twin produced less dopamine, had higher levels of an enzyme called monoamine oxidase B (MAO-B), and poor ability to connect with each other. Treating the neurons with molecules that lowered the activity of MAO-B together with overexpressed GBA normalized -synuclein and dopamine levels in the cell models. This suggests that a combination therapy for the affected twin may be possible by simultaneously targeting these two enzymes.

"The subject of Parkinson's disease discordant twins gave us an incredible opportunity to utilize stem cell models of disease in a dish to unlock some of the biological mechanisms of disease," said Dr. Scott Noggle, NYSCF Vice President, Stem Cell Research and The NYSCF - Charles Evans Senior Research Fellow for Alzheimer's Disease. "Working with these various different groups and scientists added to the depth and value of the research and we hope our findings will be applicable to other Parkinson's disease patients and other neurodegenerative disorders."

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Scientists create Parkinson's disease in a dish