TAG: "Genetics"

Tackling rare diseases


UC Irvine researchers’ search for genetic clues is giving new hope to families.

“In our lab, we don’t give up,” says Virginia Kimonis, a UC Irvince specialist in rare genetic diseases. “If people are reaching out, you have to do all you can about rare diseases.” (Photo by Steve Zylius, UC Irvine)

By the time families meet with Dr. Virginia Kimonis, hope is about all they have left.

Her pediatric patients are afflicted with debilitating diseases caused by mutations in an alphabet soup of genes – VCP and NUBPL among them. Prader-Willi, Rett, Paget’s and the like are difficult to diagnose and even harder to treat. But with cutting-edge genomic sequencing and old-fashioned scientific sleuthing, physician-researchers such as Kimonis are on the vanguard of modern medicine, finding therapies where none seemed possible.

Kimonis specializes in one of the most challenging areas: rare genetic diseases. What she and others in her field are learning about disorders that impact only a few is paving the way to a greater understanding of diseases that impact millions.

“It’s wonderful to show in the lab and in the clinic that we can offer these patients some hope,” says Kimonis, a UC Irvine pediatrician and clinical geneticist.

A rare disease is defined as one diagnosed in no more than 200,000 people worldwide; 70 percent, though, affect fewer than 6,000. And of the nearly 7,000 known rare diseases, half involve children, and 80 percent are linked to genetic flaws. These are Kimonis’ focus.

According to UC Irvine’s Dr. J. Jay Gargus, an expert in genetic metabolic diseases, rare disease research can be a springboard to understanding and treating more common ailments.

“We have a special opportunity with rare genetic diseases to provide an insight into how common diseases arise,” says Gargus, who directs the campus’s Center for Autism Research & Translation. “This is an important venue for drug discovery. The National Institutes of Health and the Food & Drug Administration recognize this and have programs established for target diseases. UC Irvine has a great strength in diagnostics, and we should be very involved in this.”

Gargus himself is making a breakthrough on a rare genetic disease. He recently held the first U.S. clinical trial of a treatment for Wolman disease, a cholesterol storage disorder, at UC Irvine Medical Center – with promising results.

Kimonis is also helping the campus establish itself as a leader in the field. She manages a section of the NIH’s Rare Diseases Clinical Research Network dedicated to Prader-Willi, Rett and Angelman syndromes.

Children with Prader-Willi – which is caused by the loss of several genes on chromosome 15 – are characterized by obesity, low muscle tone and cognitive disabilities. In addition to treating Prader-Willi patients with novel approaches, Kimonis is building a national database of those with the disease and designing studies to identify promising therapies.

In one project, she plans to partner with Daniele Piomelli – UC Irvine’s Louise Turner Arnold Chair in the Neurosciences, who examines the endocannabinoid system – to see how marijuana-like chemicals called OEAs created in the body can help curb the insatiable appetites of Prader-Willi children. By creating mice models with Prader-Willi gene mutations, the two hope to learn if the hunger-curbing signal provided by OEA is missing and whether compounds that boost OEA can aid satiety.

“If successful, our experiments will achieve two important objectives,” Piomelli says. “First, they will help us understand why Prader-Willi causes hunger; second, and more importantly, they will suggest new possible therapies to reduce appetite.”

Another focus of Kimonis’ work centers on disorders triggered by mutations in the valosin-containing protein gene. VCP programs enzymes that help maintain cell health by breaking down and clearing away old and damaged proteins that are no longer necessary. Mutations in the VCP gene have been discovered in people who have a muscle-weakening disease called inclusion body myopathy, early-onset Paget’s disease of the bone or frontotemporal dementia.

Kimonis was the first scientist to map and identify mutations in the VCP gene in inclusion body myopathy, and in 2012, she developed the first genetically modified mouse model that exhibits many of the clinical features of diseases largely caused by VCP gene mutations.

“Mouse models like these are important because they let researchers study how these now-incurable, degenerative disorders progress in vivo and will provide a platform for translational studies that could lead to lifesaving treatments,” says Kimonis, who co-directs UC Irvine’s MitoMed laboratory, which offers testing for many rare diseases.

Her research breakthroughs are coinciding with greater public recognition of rare genetic diseases. The NIH has established an Office of Rare Diseases Research, and nonprofit groups such as the Orange County-based Global Genes Project are increasing awareness, advocating and soliciting philanthropic aid on behalf of this issue. (The GGP is hosting a patient advocacy summit Sept. 11 and 12 in Huntington Beach.)

Parents of children with rare genetic diseases are also speaking out. Cristy and Rick Spooner of Rancho Santa Margarita, who’ve endured a long quest to identify a disabling condition affecting two of their three daughters, have gone public with their story, hoping to raise the profile of such diseases.

After the Spooners spent years seeking help from doctors, Kimonis contacted them about a new technique, called exome sequencing, that examines the tens of thousands of genes in the human body for disease-causing mutations. Aliso Viejo-based Ambry Genetics, which partners with Kimonis’ research group, provided the sequencing services.

Test results showed that Cali and Ryann Spooner harbored mutations in the NUBPL gene. This defect prevents their mitochondria – the power generators in cells – from efficiently producing energy. Armed with this information, Kimonis developed dietary and drug treatments for the Spooner sisters.

“What’s even more satisfying about our work is that it has huge implications for other diseases,” she says.

Kimonis is seeking funding to determine whether mitochondrial defects caused by mutated NUBPL genes underlie the onset of Parkinson’s disease. She hopes to partner with UC Irvine neurologist Dr. Neal Hermanowicz, who manages the movement disorders program, to establish a clinical research network for this effort.

“In our lab, we don’t give up,” Kimonis says. “If people are reaching out, you have to do all you can about rare diseases.”

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Target ID’d for rare inherited neurological disease in men


Finding provides insight for Kennedy’s disease, other neurodegenerative diseases.

Researchers at the UC San Diego School of Medicine have identified the mechanism by which a rare, inherited neurodegenerative disease causes often crippling muscle weakness in men, in addition to reduced fertility.

The study, published today (Aug. 10) in the journal Nature Neuroscience, shows that a gene mutation long recognized as a key to the development of Kennedy’s disease impairs the body’s ability to degrade, remove and recycle clumps of “trash” proteins that may otherwise build up on neurons, progressively impairing their ability to control muscle contraction. This mechanism, called autophagy, is akin to a garbage disposal system and is the only way for the body to purge itself of non-working, misshapen trash proteins.

“We’ve known since the mid-1990s that Alzheimer’s disease, Parkinson’s disease and Huntington’s disease are caused by the accumulation of misfolded proteins that should have been degraded, but cannot be turned over,” said senior author Albert La Spada, M.D., Ph.D. and professor of pediatrics, cellular and molecular medicine, and neurosciences. “The value of this study is that it identifies a target for halting the progression of protein build-up, not just in this rare disease, but in many other diseases that are associated with impaired autophagy pathway function.”

Of the 400 to 500 men in the U.S. with Kennedy’s disease, the slow but progressive loss of motor function results in about 15 to 20 percent of those with the disease becoming wheelchair bound during later stages of the disease.

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Researchers ID gene mutation for heart disease in Newfoundland dogs


Information could help gradually eliminate the disease from the breed.

Newfoundlands — those massive, furry, black dogs — have captured many a heart with their hallmark size, sweet nature and loyalty. Unfortunately these gentle giants’ own hearts are all too often afflicted with a potentially lethal congenital disease called subvalvular aortic stenosis, or SAS, which also affects children and other dog breeds including the golden retriever.

A team of researchers led by UC Davis veterinary cardiologist Joshua Stern has for the first time identified a gene mutation responsible for canine SAS, the most common inherited heart disease in dogs. The study appears online in the journal Human Genetics: www.ncbi.nlm.nih.gov/pubmed/24898977.

“Our hope now is that breeders will be able to make informed breeding decisions and avoid breeding dogs that harbor this mutation, thus gradually eliminating the disease from the Newfoundland breed,” Stern said. “In addition, now that we know one gene responsible for SAS and more about which proteins are involved, we can move forward to consider novel therapies that may help treat this devastating condition.”

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UC Irvine study offers new leads for liver disease treatments


Genomic partitioning by biological clock separates key metabolic functions.

Much of the liver’s metabolic function is governed by circadian rhythms – our own body clock – and UC Irvine researchers have now found two independent mechanisms by which this occurs.

The study, published online today (July 31) in Cell, reveals new information about the body clock’s sway over metabolism and points the way to more focused drug treatments for liver disease and such metabolic disorders as obesity and diabetes.

Paolo Sassone-Corsi, UCI’s Donald Bren Professor of Biological Chemistry, and postdoctoral scholar Selma Masri report that two of these circadian-linked proteins, SIRT1 and SIRT6, manage important liver processes – lipid storage and energy usage in liver cells – separately and distinctly from each other.

This surprising discovery of genomic partitioning, Masri noted, reveals how strictly regulated circadian control of metabolism can be.

“The ability of the genome and epigenome to cross-talk with metabolic pathways is critical for cellular and organismal functions. What’s remarkable is that the circadian clock is intimately involved in this dialogue,” she said.

Circadian rhythms of 24 hours govern fundamental physiological functions in virtually all organisms. The circadian clocks are intrinsic time-tracking systems in our bodies that anticipate environmental changes and adapt themselves to the appropriate time of day. Changes to these rhythms can profoundly influence human health. Up to 15 percent of people’s genes are regulated by the day-night pattern of circadian rhythms; nearly 50 percent of those involved with metabolic pathways in the liver are influenced by these rhythms.

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Gene behind rare birth abnormality provides a window on evolution


Fine-tuning genes shapes teeth as evolution did.

Ophir Klein, UC San Francisco

A UC San Francisco physician who treats birth defects affecting the face has teamed up with a European expert on animal evolution to create rodent teeth that harken back in evolutionary time.

By making a molar that mimics features found in an ancestral uber-rodent that roamed the earth 60 million years ago, the scientists successfully demonstrated a new way to explore how genetic changes affect mammalian development and how advantageous genetic mutations that spontaneously arise in new generations might take hold over time in an evolving population.

It’s not Jurassic Park, but the research team showed that real-time lab experiments are relevant to paleontologists, who typically are stuck working on mysteries of evolution equipped with little more than bits of fossilized bone or teeth. Especially for mammals, the fine features of teeth are used to determine how fossil species are related to each other and to modern animals.

A key gene manipulated by the researchers in their new study, published online today (July 30) in Nature, already had been a clinical research focus of study co-senior author Ophir Klein, M.D., Ph.D., Larry L. Hillblom Distinguished Professor in Craniofacial Anomalies at UCSF. The gene, Eda, encodes a developmental protein called ectodysplasin. It is defective in a rare human birth defect that results in a shortage or absence of sweat glands, misshapen and absent teeth, and loss of hair follicles – all appendages that develop from the same embryonic tissue. The syndrome was even described by Charles Darwin in “The Variation of Animals and Plants Under Domestication,” published in 1868.

Researchers in Switzerland had previously found that the syndrome in mice can be treated during the mother’s gestation by administering the missing ectodysplasin — the first demonstration that a structural birth defect could be prevented with a medical approach, Klein said.

Klein led the first phase I clinical trial to similarly treat the condition in humans, and this past November treated the first North American baby in an ongoing phase II study.

But Klein and collaborator Jukka Jernvall, Ph.D., Academy Professor of evolution and development at the University of Helsinki, Finland, had also been wondering if the same biochemical pathway also could be manipulated to study evolution.

In the past, biologists have studied fine features of teeth in mutant animals to try to help them reconstruct evolutionary history. However, the changes in the mutants are often too dramatic to be very informative. “We wanted to know if we could play with these biochemical pathways to recapitulate changes that are seen in the fossil record,” Klein said.

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Friends are the family you choose


Genome-wide analysis reveals genetic similarities among friends.

A genome-wide analysis by researchers and friends James Fowler (right) and Nicholas Christakis shows that pairs of friends share genetic similarities. (Photo by Liza Green)

If you consider your friends family, you may be on to something. A study from UC San Diego and Yale University finds that friends who are not biologically related still resemble each other genetically.

Published in the Proceedings of the National Academy of Sciences, the study is co-authored by James Fowler, professor of medical genetics and political science at UC San Diego, and Nicholas Christakis, professor of sociology, evolutionary biology and medicine at Yale.

“Looking across the whole genome,” Fowler said, “we find that, on average, we are genetically similar to our friends. We have more DNA in common with the people we pick as friends than we do with strangers in the same population.”

The study is a genome-wide analysis of nearly 1.5 million markers of gene variation, and relies on data from the Framingham Heart Study. The Framingham dataset is the largest the authors are aware of that contains both that level of genetic detail and information on who is friends with whom.

The researchers focused on 1,932 unique subjects and compared pairs of unrelated friends against pairs of unrelated strangers. The same people, who were neither kin nor spouses, were used in both types of samples. The only thing that differed between them was their social relationship.

The findings are not, the researchers say, an artifact of people’s tendency to befriend those of similar ethnic backgrounds. The Framingham data is dominated by people of European extraction. While this is a drawback for some research, it may be advantageous to the study here: because all the subjects, friends and not, were drawn from the same population. The researchers also controlled for ancestry, they say, by using the most conservative techniques currently available. The observed genetic go beyond what you would expect to find among people of shared heritage – these results are “net of ancestry,” Fowler said.

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Extinct human cousin gave Tibetans advantage at high elevation


First time a gene from another species of human shown to help modern humans adapt to environment.

Tibetan boy (Photo courtesy of BGI-Shenzen, China)

Tibetans were able to adapt to high altitudes thanks to a gene picked up when their ancestors mated with a species of human they helped push to extinction, according to a new report by University of California, Berkeley, scientists.

This is the first time a gene from another species of human has been shown unequivocally to have helped modern humans adapt to their environment, the researchers said.

An unusual variant of a gene involved in regulating the body’s production of hemoglobin – the molecule that carries oxygen in the blood – became widespread in Tibetans after they moved onto the high-altitude plateau several thousand years ago. This variant allowed them to survive despite low oxygen levels at elevations of 15,000 feet or more, whereas most people develop thick blood at high altitudes, leading to cardiovascular problems.

“We have very clear evidence that this version of the gene came from Denisovans,” a mysterious human relative that went extinct 40,000-50,000 years ago, around the same time as the more well-known Neanderthals, under pressure from modern humans, said principal author Rasmus Nielsen, UC Berkeley professor of integrative biology. “This shows very clearly and directly that humans evolved and adapted to new environments by getting their genes from another species.”

Nielsen and his colleagues at BGI-Shenzhen in China, the world’s largest genome sequencing center, will report their findings online today (July 2) in advance of publication in the journal Nature.

The gene, called EPAS1, is activated when oxygen levels in the blood drop, triggering production of more hemoglobin. The gene has been referred to as the “superathlete” gene because at low elevations, some variants of it help athletes quickly boost hemoglobin and thus the oxygen-carrying capacity of their blood, upping endurance. At high altitudes, however, the common variants of the gene boost hemoglobin and its carrier, red blood cells, too much, increasing the thickness of the blood and leading to hypertension and heart attacks as well as low birth weight babies and increased infant mortality. The variant, or allele, found in Tibetans raises hemoglobin and red blood cell levels only slightly at high elevations, avoiding the side effects seen in most people who relocate to elevations above 13,000 feet.

“We found that part of the EPAS1 gene in Tibetans is almost identical to the gene in Denisovans and very different from all other humans,” Nielsen said. “We can do a statistical analysis to show that this must have come from Denisovans. There is no other way of explaining the data.”

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UCLA awarded $7M to unravel mystery genetic diseases


One of six institutions chosen by NIH to help tackle the most difficult-to-solve medical cases.

The David Geffen School of Medicine at UCLA is one of six institutions nationwide chosen by the National Institutes of Health to join the agency’s efforts to tackle the most difficult-to-solve medical cases and develop ways to diagnose rare genetic disorders.

Part of a $120 million initiative called the Undiagnosed Diseases Network, the $7.2 million grant to UCLA will support comprehensive “bedside-to-bench” clinical research to aid physicians in their efforts to give long-sought answers to patients living with mystery diseases.

“Undiagnosed diseases take a huge toll on patients, their families and the health care system,” said Katrina Dipple, a co-principal investigator on the UCLA grant with Stanley Nelson, Christina Palmer and Eric Vilain. “This funding will accelerate and expand our clinical genomics program, enabling us to quickly give patients a firm diagnosis and clarify the best way to treat them.”

Despite extensive clinical testing by skilled physicians, some diseases remain unrecognized because they are extremely rare, underreported or atypical forms of more common diseases. An interdisciplinary team of geneticists at each Undiagnosed Diseases Network site will examine and study patients with prolonged undiagnosed diseases.

“A vast number of children and adults suffer from severe, often fatal, undiagnosed disorders,” Vilain said. “This program will enable us to discover new genes causing ultra-rare medical conditions and to identify environmental factors that lead to disease or that interact with genes to cause disease.”

Patients will undergo an intensive weeklong clinical assessment that includes a clinical evaluation, consultations with specialists, and medical tests, including genome sequencing to identify genetic mutations. The team will also evaluate the impact on patients and families of genetic counseling and genomic test results to develop best practices for conveying this information.

The Undiagnosed Diseases Network capitalizes on the strengths of UCLA’s genetic medicine program, particularly its Clinical Genomics Center, which utilizes powerful sequencing technology to diagnose rare genetic disorders. Using a simple blood sample from a patient and both parents, the center can perform a test that simultaneously searches 37 million base pairs in 20,000 genes to pinpoint the single DNA change responsible for causing a patient’s disease. To date, a specific genetic explanation has been identified in a quarter of the cases evaluated with this test, as have a number of novel disease-causing genes.

UCLA is the only facility in the western U.S. and one of only three nationwide with a laboratory that can perform genomic sequence directly usable for patient care, and the university’s Medical Genetics Clinic cares for more than 750 new patients a year and offers comprehensive pre- and post-test genetic counseling.

All patient studies will take place at UCLA’s Westwood campus, at the Clinical and Translational Research Center of the Clinical and Translational Science Institute. Network investigators will share genomic and clinical data gleaned from patients with their research colleagues nationwide to enhance the understanding of rare and unknown diseases.

Patients interested in participating in the Undiagnosed Diseases Network may learn more at www.rarediseases.info.nih.gov/undiagnosed. Applications will be accepted beginning in the fall.

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Families with an autistic child are a third less likely to have more kids


UCSF study has implications for studying the genetic basis and risk of the disorder.

Neil Risch, UC San Francisco

Parents who have a child with autism spectrum disorder (ASD) are about one-third less likely to have more children than families without an affected child, according to a study led by a UC San Francisco researcher.

The findings, which appear in today’s (June 18) issue of JAMA Psychiatry, stem from the largest study of its kind on further child bearing after a child has been diagnosed with the disorder. These are the first data to indicate that this is a reproductive decision. “While it has been postulated that parents who have a child with ASD may be reluctant to have more children, this is first time that anyone has analyzed the question with hard numbers,” said Neil Risch, Ph.D., a UCSF professor of epidemiology and biostatistics and director of the UCSF Institute for Human Genetics.

Most previous research into the heredity of autism has ignored a possible decision on the part of parents with affected children to reduce their subsequent child-bearing, a situation that occurs with some birth defects and has been termed “reproductive stoppage.” As a result, previous estimates of the odds of having a second child with the disorder may have made the risk appear lower than it actually is.

“This study is the first to provide convincing statistical evidence that reproductive stoppage exists and should be taken into account when calculating the risks for having a another child with ASD,” said Risch, who is senior author on the paper. “These findings have important implications for genetic counseling of affected families.”

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Your genes affect your betting behavior


Decisions influenced by variants of dopamine-regulating genes in a person’s brain.

Investors and gamblers take note: your betting decisions and strategy are determined, in part, by your genes.

University of California, Berkeley, and University of Illinois at Urbana-Champaign (UIUC) researchers have shown that betting decisions in a simple competitive game are influenced by the specific variants of dopamine-regulating genes in a person’s brain.

Dopamine is a neurotransmitter – a chemical released by brain cells to signal other brain cells – that is a key part of the brain’s reward and pleasure-seeking system. Dopamine deficiency leads to Parkinson’s disease, while disruption of the dopamine network is linked to numerous psychiatric and neurodegenerative disorders, including schizophrenia, depression and dementia.

While previous studies have shown the important role of the neurotransmitter dopamine in social interactions, this is the first study tying these interactions to specific genes that govern dopamine functioning.

“This study shows that genes influence complex social behavior, in this case strategic behavior,” said study leader Ming Hsu, an assistant professor of marketing in UC Berkeley’s Haas School of Business and a member of the Helen Wills Neuroscience Institute. “We now have some clues about the neural mechanisms through which our genes affect behavior.”

The implications for business are potentially vast but unclear, Hsu said, though one possibility is training workforces to be more strategic. But the findings could significantly affect our understanding of diseases involving dopamine, such as schizophrenia, as well as disorders of social interaction, such as autism.

“When people talk about dopamine dysfunction, schizophrenia is one of the first diseases that come to mind,” Hsu said, noting that the disease involves a very complex pattern of social and decision making deficits. “To the degree that we can better understand ubiquitous social interactions in strategic settings, it may help us understand how to characterize and eventually treat the social deficits that are symptoms of diseases like schizophrenia.”

Hsu, UIUC graduate student Eric Set and their colleagues, including Richard P. Ebstein and Soo Hong Chew from the National University of Singapore, will publish their findings the week of June 16 in the online early edition of the Proceedings of the National Academy of Sciences.

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Mexican genetics study reveals huge variation in ancestry


UCSF/Stanford team uncovers basis for health differences among Latinos.

In the most comprehensive genetic study of the Mexican population to date, researchers from UC San Francisco and Stanford University, along with Mexico’s National Institute of Genomic Medicine (INMEGEN), have identified tremendous genetic diversity, reflecting thousands of years of separation among local populations and shedding light on a range of confounding aspects of Latino health.

The study, which documented nearly 1 million genetic variants among more than 1,000 individuals, unveiled genetic differences as extensive as the variations between some Europeans and Asians, indicating populations that have been isolated for hundreds to thousands of years.

These differences offer an explanation for the wide variety of health factors among Latinos of Mexican descent, including differing rates of breast cancer and asthma, as well as therapeutic response. Results of the study, on which UCSF and Stanford shared both first and senior authors, appear in the June 13 online edition of the journal Science.

“Over thousands of years, there’s been a tremendous language and cultural diversity across Mexico, with large empires like the Aztec and Maya, as well as small, isolated populations,” said Christopher Gignoux, Ph.D., who was first author on the study with Andres Moreno-Estrada, M.D., Ph.D., first as a graduate student at UCSF and now as a postdoctoral fellow at Stanford. “Not only were we able to measure this diversity across the country, but we identified tremendous genetic diversity, with real disease implications based on where, precisely, your ancestors are from in Mexico.”

For decades, physicians have based a range of diagnoses on patients’ stated or perceived ethnic heritage, including baseline measurements for lung capacity, which are used to assess whether a patients’ lungs are damaged by disease or environmental factors. In that context, categories such as Latino or African-American, both of which reflect people of diverse combinations of genetic ancestry, can be dangerously misleading and cause both misdiagnoses and incorrect treatment.

While there have been numerous disease/gene studies since the Human Genome Project, they have primarily focused on European and European-American populations, the researchers said. As a result, there is very little knowledge of the genetic basis for health differences among diverse populations.

“In lung disease such as asthma or emphysema, we know that it matters what ancestry you have at specific locations on your genes,” said Esteban González Burchard, M.D., M.P.H., professor of bioengineering and therapeutic sciences, and of medicine, in the UCSF schools of pharmacy and medicine. Burchard is co-senior author of the paper with Carlos Bustamante, Ph.D., a professor of genetics at Stanford. “In this study, we realized that for disease classification it also matters what type of Native American ancestry you have. In terms of genetics, it’s the difference between a neighborhood and a precise street address.”

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Researchers discover new gene involved in Parkinson’s disease


UCLA finding may lead to new target for treatment.

Ming Guo, UCLA

In the past decade, scientists have identified a handful of genes connected with Parkinson’s disease. Now, a team of UCLA researchers has identified another gene involved in the neurological disorder. Their finding may provide a target for drugs that could one day prevent or even cure the debilitating illness.

Parkinson’s disease is the second most common neurodegenerative disorder, after Alzheimer’s disease, and it has no cure. About 60,000 Americans are diagnosed with Parkinson’s disease each year, and it is estimated that as many as 1 million Americans live with Parkinson’s disease – more than the number of people with multiple sclerosis, muscular dystrophy and Lou Gehrig’s disease combined.

In Parkinson’s disease, multiple neurons in the brain gradually break down or die, causing patients to experience tremors, rigidity, slowness in movement and difficulty walking, as well as depression, anxiety, sleeping difficulties and dementia, said Dr. Ming Guo, the study’s team leader, a UCLA associate professor of neurology and pharmacology.

In 2006, Guo’s team was one of two groups that first reported that two genes, PTEN-induced putative kinase 1 (PINK1) and Parkin, act together to maintain the health of mitochondria – which power the neurons that are important for maintaining brain health. Mutations in these genes lead to early-onset Parkinson’s disease.

Guo’s team also showed that when the PINK1 and Parkin genes are operating correctly, they help maintain the regular shape of healthy mitochondria and help cells eliminate damaged mitochondria. The accumulation of unhealthy or damaged mitochondria in neurons and muscles ultimately results in Parkinson’s disease.

In the new study, Guo and her colleagues found that a gene called MUL1 (also known as MULAN and MAPL) plays an important role in mediating the pathology of the PINK1 and Parkin. The study, performed in fruit flies and mice, showed that providing an extra amount of MUL1 helps reduce the amount of damage that mutated PINK/Parkin create in mitochondria, and that inhibiting MUL1 in mutant PINK1/Parkin exacerbates the damage to the mitochondria.  In addition, Guo and her collaborators found that removing MUL1 from mouse neurons of the Parkin disease model results in unhealthy mitochondria and degeneration of the neurons.

“We show that MUL1 dosage is key and optimizing its function is crucial for brain health and to ward off Parkinson’s disease,” said Guo, a practicing neurologist at UCLA. “Our work proves that mitochondrial health is of central importance to keep us from suffering from neurodegeneration. Further, finding a drug that can enhance MUL1 function would be of great benefit to patients with Parkinson’s disease.”

The five-year study was published June 4 in eLife, an open-access journal for biomedical and life sciences research.

“This finding is a major advance in Parkinson’s disease research,” Guo said. “There are several implications to this work, including that MUL1 appears to be a very promising drug target and that it may constitute a new pathway regulating the quality of mitochondria.”

Guo and her team plan to test their results in more complex organisms, hoping to understand more about how MUL1 works. Additionally, the team will work on identifying compounds that could specifically target MUL1 and examine whether mutations in MUL1 exist in some people with inherited forms of Parkinson’s.

The study was a collaboration between Guo’s lab and Dr. Zuhang Sheng of the National Institutes of Health, and was supported by the National Institute of Aging (R01, K02), the National Institute of Neurological Disorders and Stroke (EUREKA award), an Ellison Medical Foundation Senior Scholar Award, the McKnight Neuroscience Foundation, the Klingenstein Foundation, the American Parkinson’s Disease Association and the Glenn Family Foundation.

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