TAG: "Huntington’s disease"

Scientists hunt down origin of Huntington’s disease in the brain

UCLA research suggests new targets, routes for drugs to slow the devastating disease.

The gene mutation that causes Huntington’s disease appears in every cell in the body, yet it kills only two types of brain cells. Why? UCLA scientists used a unique approach to switch the gene off in individual brain regions and zero in on those that play a role in causing the disease in mice.

Published in today’s (April 28) online edition of the journal Nature Medicine, the research sheds light on where Huntington’s starts in the brain. It also suggests new targets and routes for therapeutic drugs to slow the devastating disease, which strikes an estimated 35,000 Americans.

“From Day One of conception, the mutant gene that causes Huntington’s appears everywhere in the body, including every cell in the brain,” said X. William Yang, a professor of psychiatry and biobehavioral sciences at the Semel Institute for Neuroscience and Human Behavior at UCLA. “Before we can develop effective strategies to treat the disorder, we need to first identify where it starts and how it ravages the brain.”

Huntington’s disease is passed from parent to child through a mutation in a gene called huntingtin. Scientists blame a genetic “stutter” — a repetitive stretch of DNA at one end of the altered gene — for the cell death and the brain atrophy that progressively deprives patients of their ability to move, speak, eat and think clearly. No cure exists, and people with aggressive cases may die in as little as 10 years.

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Tweaking potassium levels in brain could be a key to fighting Huntington’s

UCLA findings could point to new drug targets for treating the devastating disease.

Astrocytes in brain tissue

By boosting the ability of a specific type of cell to absorb potassium in the brain, UCLA researchers were able to improve walking and prolong survival in a mouse model of Huntington’s disease.

Their findings, published March 30 in the online edition of the journal Nature Neuroscience, could point to new drug targets for treating the devastating disease, which strikes one in every 20,000 Americans.

Huntington’s disease is passed from parent to child through a mutation in the huntingtin gene. By killing brain cells called neurons, the disorder gradually deprives patients of their ability to walk, speak, swallow, breathe and think clearly. No cure exists, and patients with aggressive cases can die in as little as 10 years.

The laboratories of Baljit Khakh, a UCLA professor of physiology and neurobiology, and Michael Sofroniew, a UCLA professor of neurobiology, teamed up at the David Geffen School of Medicine at UCLA to unravel the role that astrocytes — large, star-shaped cells found in the brain and spinal cord — play in Huntington’s.

“Astrocytes appear in the brain in equal numbers to neurons yet haven’t been closely studied,” Khakh said. “They enable neurons to signal each other by maintaining an optimal chemical environment outside the cells. We used two mouse models to explore whether astrocytes behave differently during Huntington’s disease.”

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Single gene mutation linked to neurological disorders

From Lesch-Nyhan syndrome to Alzheimer’s, Parkinson’s and Huntington’s diseases.

Theodore Friedmann, UC San Diego

Theodore Friedmann, UC San Diego

A research team, headed by Theodore Friedmann, M.D., professor of pediatrics at the UC San Diego School of Medicine, says a gene mutation that causes a rare but devastating neurological disorder known as Lesch-Nyhan syndrome appears to offer clues to the developmental and neuronal defects found in other, diverse neurological disorders like Alzheimer’s, Parkinson’s and Huntington’s diseases.

The findings, published in today’s (Oct. 9) issue of the journal PLOS ONE, provide the first experimental picture of how gene expression errors impair the ability of stem cells to produce normal neurons, resulting instead in neurological disease. More broadly, they indicate that at least some distinctly different neurodevelopmental and neurodegenerative disorders share basic, causative defects.

The scientists say that understanding defects in Lesch-Nyhan could help identify errant processes in other, more common neurological disorders, perhaps pointing the way to new kinds of therapies.

Lesch-Nyhan syndrome is caused by defects in the HPRT1 gene (short for hypoxanthine guanine phosphoribosyltransferace, the enzyme it encodes), a gene that is well-known for its essential “housekeeping duties,” among them helping generate purine nucleotides – the building blocks of DNA and RNA.

Mutations in the gene result in deficiencies in the HPRT enzyme, leading to defective expression of the neurotransmitter dopamine and subsequent abnormal neuron function. HPRT mutation is known to be the specific cause of Lesch-Nyhan, an inherited neurodevelopmental disorder characterized by uncontrollable repetitive body movements, cognitive defects and compulsive self-mutilating behaviors. The disorder was first described in 1964 by medical student Michael Lesch and his mentor, William Nyhan, M.D., professor emeritus at UC San Diego School of Medicine.

Using mouse embryonic stem cells modified to be HPRT-deficient, Friedmann and colleagues discovered that the cells do not develop normally. Instead, they differentiate from full-fledged neurons into cells that resemble and partially function as neurons, but also perform functions more typical of glial cells, a kind of supporting cell in the central nervous system. In addition, they noted that HPRT deficiency causes abnormal regulation of many cellular functions controlling important operational and reproduction mechanisms, DNA replication and repair and many metabolic processes.

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Failure to destroy toxic protein contributes to progression of Huntington’s

Study also finds target that boosts protein clearance, prolongs cell life.

Steve Finkbeiner

Steve Finkbeiner

Alzheimer’s, Huntington’s, Parkinson’s.

Names forever linked to what they represent: diseases that ravage the brain’s neurons and leave entire regions to wither and die. These and other so-called neurodegenerative diseases are often associated with the buildup of toxic proteins that lead to neuronal death.

But now, scientists at the Gladstone Institutes have discovered that the progression of disease is not due to the buildup of toxins itself, but rather in the individual neurons’ ability to dissolve them. Further, they have identified a therapeutic target that could boost this ability, thereby protecting the brain from the diseases’ deadly effects.

In the latest issue of Nature Chemical Biology, researchers in the laboratory of Gladstone investigator Steve Finkbeiner, M.D., Ph.D., describe how a newly developed technology allowed them to see – for the first time – how individual neurons fight back against the buildup of toxic proteins over time. Focusing their efforts on a model of Huntington’s disease, the team observed how different types of neurons in the brain each responded to this toxic buildup with different degrees of success, offering clues as to why the disease causes neurons in one region to die, while neurons in another are spared.

“Huntington’s – an inherited and fatal disorder that leads to problems with muscle coordination, cognition and personality – is characterized by the toxic buildup of a mutant form of the huntingtin protein in the brain,” explained Finkbeiner, who directs the Taube-Koret Center for Neurodegenerative Disease Research at Gladstone. Finkbeiner is also a professor of neurology and physiology at UC San Francisco, with which Gladstone is affiliated.

“A long-standing mystery among researchers was how the buildup of this mutant huntingtin caused cells to degrade and die, but previous technology made it virtually impossible to monitor this process at the cellular level,” he added. “In this study, we employed a method called optical pulse-labeling, or OPL, which allowed us to see how the mutant huntingtin ravaged the brain over time – neuron by neuron.”

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UC Irvine studies point to new targets for Huntington’s disease treatments

Studies reveal fundamental mechanism of diseases related to the human brain.

Leslie Thompson, UC Irvine

Leslie Thompson, UC Irvine

UC Irvine MIND’s Leslie Thompson has worked on Huntington’s disease for over two decades, and her group’s research has revealed extensive insights into the biological underpinnings of the disease. Now, her laboratory adds to its impressive log of discoveries.

Thompson is the lead author for studies appearing the week of July 15 in the Proceedings of the National Academy of Sciences and Cell Reports that identify new and well-defined molecular targets for drugs that can treat the fatal neurodegenerative disease.

In the journal Cell Reports, published today (July 18), Thompson and colleagues identify how two proteins – SUMO-2 and PIAS1 – help control the accumulation of the Huntingtin protein in brain tissue. This accumulation is central to disease progression. And in the PNAS article, also published this online week, Thompson and colleagues explore the genetics of HD, reporting that targeting a histone-modifying enzyme (H3K4 demethylase) can normalize the expression of certain aberrant genes that promote disease progression.

“The molecular activities we identified represent defined therapeutic targets,” says Thompson, a professor of psychiatry & human behavior and neurobiology & behavior. “However, they also both reveal fundamental mechanism of diseases related to the human brain, and underscore the importance of basic science research on neurodegenerative diseases.”

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Mapping technique uncovers underlying circuit architecture of the brain

Study to help scientists decode circuitry that guides brain function.

Anatol Kreitzer

The power of the brain lies in its trillions of intercellular connections, called synapses, which together form complex neural “networks.”

While neuroscientists have long sought to map these complex connections to see how they influence specific brain functions, traditional techniques have yet to provide the desired resolution.

Now, by using an innovative brain-tracing technique, scientists at the Gladstone Institutes and the Salk Institute have found a way to untangle these networks. Their findings offer new insight into how specific brain regions connect to each other, while also revealing clues as to what may happen, neuron by neuron, when these connections are disrupted.

In the latest issue of Neuron, a team led by Gladstone investigator Anatol Kreitzer, Ph.D., and Salk investigator Edward Callaway, Ph.D., combined mouse models with a sophisticated tracing technique — known as the monosynaptic rabies virus system — to assemble brain-wide maps of neurons that connect with the basal ganglia, a region of the brain that is involved in movement and decision-making. Developing a better understanding of this region is important as it could inform research into disorders causing basal ganglia dysfunction, including Parkinson’s disease and Huntington’s disease.

“Taming and harnessing the rabies virus – as pioneered by Dr. Callaway – is ingenious in the exquisite precision that it offers compared with previous methods, which were messier with a much lower resolution,” explained Kreitzer, who is also an associate professor of neurology and physiology at UC San Francisco, with which Gladstone is affiliated. “In this paper, we took the approach one step further by activating the tracer genetically, which ensures that it is only turned on in specific neurons in the basal ganglia. This is a huge leap forward technologically, as we can be sure that we’re following only the networks that connect to particular kinds of cells in the basal ganglia.”

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A cause close to her heart

UC Irvine staffer works to end Huntington’s disease.

Frances Saldana, UC Irvine

Frances Saldana, UC Irvine

For two decades, UC Irvine has been on the forefront of Huntington’s disease research and care, and Frances Saldaña is working to keep it that way.

By day, she manages the Corporate Partners program for The Paul Merage School of Business. But Saldaña is better known as a focused and driven advocate for the patients and family members who must endure the terrible consequences of this incurable neurodegenerative disorder.

She shares their pain. Saldaña has lost a husband and her younger daughter to Huntington’s disease, and her other two children are in the late stages of it. “HD is cruel and unfair,” she says. “And we have to end it.”

So along with friends Jean Abdalla and Linda Pimental, who have also lost family members to the disease, Saldaña founded HD CARE to raise awareness and funds for UC Irvine research and clinical care. It’s an official support group of the campus’s Institute for Memory Impairments & Neurological Disorders (UCI MIND), which explores new research and treatments for a spectrum of neurodegenerative diseases, including Alzheimer’s and Parkinson’s.

“Frances is a tireless promoter of HD research and care, and her enthusiasm is infectious,” says Leslie Thompson, a UC Irvine professor of psychiatry & human behavior and neurobiology & behavior who’s recognized as one of the world’s pre-eminent HD researchers. “Her impact is profound.”

Huntington’s disease – a progressive, genetic brain disorder – causes the degeneration of neurons in certain areas of the brain. It’s a familial disease passed from parent to child through a genetic mutation. Symptoms include uncontrolled movements, loss of intellectual capabilities and emotional disturbances. In the U.S. alone, at least 30,000 people have HD, and more than 150,000 others have a 50 percent risk of developing it.

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Regulating single protein prompts fibroblasts to become neurons

Findings could have implications for developing new treatments for Parkinson’s, Alzheimer’s.

Confocal micrograph of a primary human fibroblast cell grown in culture stained blue for actin, a highly abundant protein that makes up the cytoskeleton of cells.Energy-producing mitochondria are shown in green.

Repression of a single protein in ordinary fibroblasts is sufficient to directly convert the cells – abundantly found in connective tissues – into functional neurons. The findings, which could have far-reaching implications for the development of new treatments for neurodegenerative diseases like Huntington’s, Parkinson’s and Alzheimer’s, will be published online in advance of the Jan. 17 issue of the journal Cell.

In recent years, scientists have dramatically advanced the ability to induce pluripotent stem cells to become almost any type of cell, a major step in many diverse therapeutic efforts. The new study focuses upon the surprising and singular role of PTB, an RNA-binding protein long known for its role in the regulation of alternative RNA splicing.

In in vitro experiments, scientists at the UC San Diego School of Medicine and Wuhan University in China describe the protein’s notable regulatory role in a feedback loop that also involves microRNA – a class of small molecules that modulate the expression of up to 60 percent of genes in humans. Approximately 800 miRNAs have been identified and characterized to various degrees.

One of these miRNAs, known as miR-124, specifically modulates levels of PTB during brain development. The researchers found that when diverse cell types were depleted of PTB, they became neuronal-like cells or even functional neurons – an unexpected effect. The protein, they determined, functions in a complicated loop that involves a group of transcription factors dubbed REST that silences the expression of neuronal genes in non-neuronal cells.

According to principal investigator Xiang-Dong Fu, Ph.D., professor of cellular and molecular medicine at UC San Diego, it’s not known which neuronal signal or signals turn on the loop, which in principle can happen at any point in the circle. But the ability to artificially manipulate PTB levels in cells, inducing them to become neurons, offers tantalizing possibilities for scientists seeking new treatments for an array of neurodegenerative diseases.

It is estimated that over a lifetime, 1 in 4 Americans will suffer from a neurodegenerative disease, from Alzheimer’s and Parkinson’s to multiple sclerosis and amyotrophic lateral sclerosis (Lou Gehrig’s disease).

“All of these diseases are currently incurable. Existing therapies focus on simply trying to preserve neurons or slow the rate of degeneration,” said Fu. “People are working with the idea of replacing lost neurons using embryonic stem cells, but there are a lot of challenges, including issues like the use of foreign DNA and the fact that it’s a very complex process with low efficiency.”

Fu explained that REST is expressed in cells everywhere except in neurons. PTB is itself a target of miR-124, but also acts as a break for this microRNA to attack other cellular targets that include REST, which is responsible for repressing miR-124.

In non-neuronal cells, REST keeps miR-124 down and PTB enforces this negative feedback loop, but during neural induction, miR-124 is induced, which diminishes PTB, and without PTB as a break, REST is dismantled, and without REST, additional miR-124 is produced. This loop therefore becomes a positive feed forward, which turns non-neuronal cells into neurons.

“If we learn how to manipulate PTB, which appears to be a kind of master regulator, we might eventually be able to avoid some of these problems by creating new neurons in patients using their own cells adjacent deteriorating neurons,” said Fu.

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Berkeley Lab scientists help develop promising therapy for Huntington’s

Initial results in mice could lead to new way to fight neurodegenerative diseases.

Mitochondria are labeled red and green, and the nucleus is blue, in this neuron isolated from a Huntington's disease mouse model.

There’s new hope in the fight against Huntington’s disease. A group of researchers that includes scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) have designed a compound that suppresses symptoms of the devastating disease in mice.

The compound is a synthetic antioxidant that targets mitochondria, an organelle within cells that serves as a cell’s power plant. Oxidative damage to mitochondria is implicated in many neurodegenerative diseases including Alzheimer’s, Parkinson’s and Huntington’s.

The scientists administered the synthetic antioxidant, called XJB-5-131, to mice that have a genetic mutation that triggers Huntington’s disease. The compound improved mitochondrial function and enhanced the survival of neurons. It also inhibited weight loss and stopped the decline of motor skills, among other benefits. In short, the Huntington’s mice looked and behaved like normal mice.

Based on their findings, the scientists believe that XJB-5-131 is a promising therapeutic compound that deserves further investigation as a way to fight neurodegenerative diseases.

They report their research in a paper that appears online Nov. 1 in the journal Cell Reports.

“The compound was very successful. More research is needed, but it has the real potential to make an impact in treating neurodegenerative disorders,” says Cynthia McMurray of Berkeley Lab’s Life Sciences Division. She conducted the research with other Berkeley Lab researchers, including Zhiyin Xun, and scientists from the University of Pittsburgh.

Huntington’s disease is a genetic disorder in which neurons in certain parts of the brain waste away. Symptoms of the disease typically appear in mid-life. These include loss of muscle coordination and cognitive decline. There is no cure. Currently, patients are prescribed antidepressants or compounds that reduce the loss of motor coordination, neither of which delays the disease’s progression.

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UC shares $93M in stem cell grants

Grants target CLI, Huntington’s, osteoporosis, melanoma, spinal cord injury.

The California Institute for Regenerative Medicine has approved funding for projects to be led by (from left) Nancy Lane, Vicki Wheelock, John Laird and Jan Nolta of UC Davis.

The University of California received or shared five grants totaling $93.1 million today (July 26) from the state’s stem cell agency to speed therapies to patients suffering from Huntington’s disease, critical limb ischemia, osteoporosis, melanoma and spinal cord injury. Three grants went to UC Davis researchers, one to UCLA and one was shared by UC Irvine.

The California Institute for Regenerative Medicine awarded a total of $150 million to help move promising stem cell-based therapies from laboratory research to human clinical trials.

Overall, CIRM’s governing board has awarded more than $1.5 billion in stem cell grants, with more than half of the total going to the University of California or UC-affiliated institutions.

CIRM Disease Team Therapy Development Awards:

UC Davis
: $53.1 million
, including grants of:

  • $20 million, led by Nancy Lane, targeting osteoporosis, a bone disease
  • $19 million, led by Jan Nolta and Vicki Wheelock , targeting Huntington’s disease, a genetic brain disorder
  • $14.1 million, led by John Laird and Jan Nolta, targeting critical limb ischemia, a severe blockage of the arteries

UC Irvine: $20 million for a grant shared by Aileen Anderson and Brian Cummings of UC Irvine and Nobuko Uchida of StemCells Inc., targeting cervical spinal cord injury

UCLA: $20 million for a grant led by Antoni Ribas, targeting melanoma, the most dangerous type of skin cancer

For more information:
CIRM release

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Two proteins offer ‘clearer’ way to treat Huntington’s disease

Pair helps remove, prevent misfolding of proteins that cause neurodegeneration.

In a paper published in today’s (July 11) online issue of Science Translational Medicine, researchers at the UC San Diego School of Medicine have identified two key regulatory proteins critical to clearing away misfolded proteins that accumulate and cause the progressive, deadly neurodegeneration of Huntington’s disease.

The findings explain a fundamental aspect of how the disease wreaks havoc within cells and provides “clear, therapeutic opportunities,” said principal investigator Albert R. La Spada, M.D., Ph.D., professor of cellular and molecular medicine, chief of the Division of Genetics in the Department of Pediatrics and associate director of the Institute for Genomic Medicine at UC San Diego.

“We think the implications are significant,” said La Spada. “It’s a lead we can vigorously pursue, not just for Huntington’s disease, but also for similar neurodegenerative conditions like Parkinson’s disease and maybe even Alzheimer’s disease.”

In Huntington’s disease, an inherited mutation in the huntingtin (htt) gene results in misfolded htt proteins accumulating in certain central nervous system cells, leading to progressive deterioration of involuntary movement control, cognitive decline and psychological problems. More than 30,000 Americans have Huntington’s disease. There are no effective treatments currently to either cure the disease or slow its progression.

La Spada and colleagues focused on a protein called PGC-1alpha, which helps regulate the creation and operation of mitochondria, the tiny organelles that generate the fuel required for every cell to function.

“It’s all about energy,” La Spada said. “Neurons have a constant, high demand for it. They’re always on the edge for maintaining adequate levels of energy production. PGC-1alpha regulates the function of transcription factors that promote the creation of mitochondria and allow them to run at full capacity.”

Previous studies by La Spada and others discovered that the mutant form of the htt gene interfered with normal levels and functioning of PGC-1alpha. “This study confirms that,” La Spada said. More surprising was the discovery that elevated levels of PGC-1alpha in a mouse model of Huntington’s disease virtually eliminated the problematic misfolded proteins.

Specifically, PGC-1alpha influenced expression of another protein vital to autophagy — the process in which healthy cells degrade and recycle old, unneeded or dangerous parts and products, including oxidative, damaging molecules generated by metabolism. For neurons, which must last a lifetime, the self-renewal is essential to survival.

“Mitochondria get beat up and need to be recycled,” La Spada said. “PGC-1alpha drives this pathway through another protein called transcription factor EB or TFEB. We were unaware of this connection before, because TFEB is a relatively new player, though clearly emerging as a leading actor. We discovered that even without PGC-1alpha induction, TFEB can prevent htt aggregation and neurotoxicity.”

In their experiments, Huntington’s disease mice crossbred with mice that produced greater levels of PGC-1alpha showed dramatic improvement. Production of misfolded proteins was essentially eliminated and the mice behaved normally. “Degeneration of brain cells is prevented. Neurons don’t die,” said La Spada.

PGC-1alpha and TFEB provide two new therapeutic targets for Huntington’s disease, according to La Spada. “If you can induce the bioenergetics and protein quality control pathways of nervous system cells to function properly, by activating the PGC-1alpha pathway and promoting greater TFEB function, you stand a good chance of maintaining neural function for an extended period of time. If we could achieve the level of increased function necessary to eliminate misfolded proteins, we might nip the disease process in the bud. That would go a long way toward treating this devastating condition.”

Co-authors are Taiji Tsunemi, Travis D. Ashe and Bradley E. Morrison, Department of Pediatrics, UC San Diego; Kathryn R. Soriano, Jonathan Au and Vincent A. Damian, Department of Laboratory Medicine, University of Washington; Ruben A. Vazquez Roque, Department of Pathology, UC San Diego; Eduardo R. Lazarowski, Department of Medicine, University of North Carolina; and Eliezer Masliah, Departments of Pathology and Neurosciences, UC San Diego.

Funding for this research came, in part, from the Hereditary Disease Foundation, the CHDI and the National Institutes of Health (grant numbers R01 AG033083, R01 NS065874, P01 HL034322, R01 AG018440, R01 NS057096 and R01 AG022074).

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Stem cell technology used to fight Huntington’s disease

UC Irvine, UCSF-affiliated scientists develop model to speed drug development.

Steve Finkbeiner, Gladstone Institutes

>>Related coverage: UC Irvine release

Scientists at UC Irvine, the UC San Francisco-affiliated Gladstone Institutes and an international team of researchers have generated a human model of Huntington’s disease — directly from the skin cells of patients with the disease.

For years, scientists have studied Huntington’s disease primarily in postmortem brain tissue or laboratory animals modified to mimic the disease. Today (June 28), in Cell Stem Cell, the international team shows how they developed a human model of Huntington’s disease, which causes a diverse range of neurological impairments. The new model should help scientists better understand the development of Huntington’s — and provide better ways to identify and screen potential therapeutics for this devastating disease.

This new model comes at a time of concentrated federal efforts to accelerate solutions for diseases — including a number of debilitating conditions that touch only small percentages of the population. Last year, the National Institutes of Health consolidated its efforts to attack rare diseases under the new National Center for Translational Sciences.

Huntington’s is such a rare disease, although it is the most common inherited neurodegenerative disorder. It afflicts approximately 30,000 people in the United States — with another 75,000 people carrying the gene that will eventually lead to it. Caused by a mutation in the gene for a protein called huntingtin, the disease damages brain cells so that people with Huntington’s progressively lose their ability to walk, talk, think and reason.

“An advantage of this human model is that we now have the ability to identify changes in brain cells over time — during the degeneration process and at specific stages of brain-cell development,” said Gladstone Senior Investigator Steve Finkbeiner, M.D., Ph.D. “We hope this model will help us more readily uncover relevant factors that contribute to Huntington’s disease and especially to find successful therapeutic approaches.”

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