Better Sleep May Put Huntington's Disease Sufferers Back On Track

Mice carrying the genetic mutation that causes Huntington's Disease (HD) showed marked improvements in alertness and their ability to learn after they were given drugs that put them to sleep.

Researchers at the University of Cambridge found that daily treatments of Alprazolam or chloral hydrate, two different sedative drugs, enabled them to develop a regular sleep pattern and improved their cognitive function — their ability to understand and act on information.

According to the Cambridge neuroscientists conducting the research, HD mice have abnormal circadian rhythms; their daily sleeping and waking cycles are disrupted and irregular. Since sleep disruption contributes to problems with perception and learning in healthy people, the team wondered whether the circadian disruption and cognitive disturbances in HD mice were linked.

To test this, drugs were administered to regulate sleep patterns in the mice. The results, published today in the Journal of Neuroscience, show that both drugs caused a noticeable improvement in learning and Alprazolam also improved arousal. The study shows for the first time that treatments aimed at restoring normal sleep-wake activity could slow the cognitive decline that is such a devastating feature of the disease.

Dr. Jenny Morton, lead author of the study, said: "In the future, more attention should be paid to understanding sleep and circadian disturbance in HD. Management of these patterns may not only improve patients ability to think, learn and perform, but would also improve quality of life for both them and their carers."

The results have short-and long-term implications for treatment of HD and for the reversal of the disease's impairments. Recognising that sleep disturbance is a part of the disease means that clinicians should include focussed management of sleep symptoms in their treatment of HD patients.

Myelin Implicated In Early Evolution Of Huntington's Disease

Last month, Dr. George Bartzokis, director of the UCLA Memory Disorders and Alzheimer's Disease Clinic, suggested in the journal Alzheimer's & Dementia that the breakdown of a type of myelin that develops late in life promotes the buildup of toxic amyloid plaques long associated with Alzheimer's disease. Myelin is the "insulation" that wraps around nerve axons in the brain.  

Now, in a new report posted online in the journal Neurochemical Research, Bartzokis turns his attention to Huntington's disease. Again, he suggests that a breakdown of myelin is the cause, but with a twist — it is the myelin that develops early in the formation of the brain that breaks down prematurely and eventually leads to the disease's symptoms.

Huntington's disease (HD) is a rare, inherited neurological disorder that ultimately deprives individuals of their ability to control their movement, behavior and thinking. It affects approximately 30,000 people in the U.S., with another 150,000 at risk. While it is known that HD is caused by a mutation in a gene called Huntingtin (Htt), the exact mechanism by which the Htt gene causes or contributes to neuronal cell death and HD symptoms remains unclear. Bartzokis' research suggests it is Htt's affect on myelin that may prove to be the cause. 

The earliest parts of the developing brain include systems of neurons that control movement and behavior. These neurons have long axons — finger-like projections that serve as the primary transmission lines of the nervous system — covered with thick myelin sheaths. The sheaths are nourished by an ongoing supply of a protein called brain-derived neurotrophic factor, which travels down a neuron's axon.

Bartzokis believes the Htt gene interferes with this nourishment-delivery system, resulting in a breakdown of the myelin that depends on it. That, in turn, disrupts cell signaling, which results in the neuron's death.

The problem is compounded by the continual production of other cells that continue to make myelin. In HD, increasing numbers of these cells, called oligodendrocytes, are produced in an attempt to remyelinate axons whose myelin sheaths have broken down. This results in strikingly elevated numbers of oligodendrocytes years before the appearance of HD symptoms.

Such elevation is detrimental because oligodendrocytes are rich with iron, which, while required for myelination, is also a well-known catalyst of free-radical-induced tissue damage. Iron accumulates during normal aging, and abnormal iron metabolism is believed to be involved in many human disorders. This is true for both highly prevalent, chronic disorders of aging, such as Alzheimer's and Parkinson's diseases, and acute disorders, such as stroke, where the extent of tissue damage is also related to iron levels.

To spot myelin destruction, neuron death and iron accumulation in the brains of HD subjects, Bartzokis used two magnetic resonance imaging (MRI) machines operating at different field strengths. Measurements of myelin breakdown and iron content were taken from the brains of 11 HD subjects and compared to a control group of 27subjects. Bartzokis found that both the breakdown and the iron accumulation matched the typical progression of the disease from early to late myelinating regions.

Thus, according to Bartzokis, earlier myelinated axons, such as the ones controlling movement, bear the brunt of damage from the mutant gene in the disease.

"And the early symptoms of Huntington's are problems with controlling movement, behavior and eventually thinking," he said.

The implications of this are important, Bartzokis noted, since there is a decades-long period during which therapeutic interventions could modify the course of the disease, long before clinical evidence — such as behavioral, cognitive and motor problems — appear. Thus, it may be possible to develop medication that could be administered in the very early stages using non-invasive in vivo neuroimaging markers of both myelin breakdown and levels of iron.

The research was funded by the National Institute of Mental Health; the National Institute on Aging; an Alzheimer's Disease Center grant; the California Department of Health Services; the Sidell-Kagan Foundation; and the U.S. Department of Veterans Affairs. Other authors included Po H. Lu, Todd A. Tishler, Sophia M. Fong, Bolanle Oluwadara, J. Paul Finn, Danny Huang, Yvette Bordelon, Jim Mintz and Susan Perlman, all of UCLA.

First Images Of Brain Changes Associated With Memory Revealed

University of California, Irvine researchers have developed the first images of the physical changes in brain cells thought to underlie memory, a discovery that is already uncovering clues about memory loss linked to cognitive disorders.

Three decades of work by neuroscientists have established that a physiological effect known as long-term potentiation (LTP) encodes everyday forms of memory. In the Journal of Neuroscience today, a UC Irvine research team led by neuroscientists Christine M. Gall and Gary Lynch presents these unique images, which show that the size and shape of synapses were changed by LTP.

“The way is now open to mapping where in the brain memories are laid down,” said Lynch, a professor of psychiatry and human behavior. “Seeing memory-related physical changes to synapses means that we can at last use mouse models to test if the effects of retardation, aging and various cognitive disorders involve a specific, long-suspected defect in the connections between cortical neurons.”

Brain tissue collected from rats and mice was kept alive in specially constructed equipment. The researchers induced LTP by stimulating synapses with a rhythm known to be critical to memory formation. The brain slices were then sectioned and stained with one antibody that attaches to activated proteins involved with LTP and a second one that labels synapses. Newly developed microscopic methods were used to visualize and measure synapses that had both antibodies attached.

In addition to revealing new information about the formation of memory in the brain, this study and another published last month in the Journal of Neuroscience by the UC Irvine researchers have shown how LTP deficiencies accompany the memory loss seen during the early stages of Huntington’s disease, an incurable neurodegenerative disease characterized by disturbances to memory and learning.

Lynch, Gall and colleagues found that LTP structures encoding memory are defective in mouse models of Huntington’s disease. They discovered that these synaptic defects can be fully reversed through treatment with a brain growth factor released at synapses. Ampakines, a new class of drugs developed by Lynch at UC Irvine that are currently in clinical development for Alzheimer’s disease and ADHD, increase the levels of this growth factor and potentially emerge as therapy for the cognitive problems associated with Huntington’s.

The researchers are now working to see if such LTP defects are present in mouse models of common forms of human mental retardation.

Gall is a professor of anatomy and neurobiology. Lulu Y. Chen, Christopher S. Rex, Malcolm S. Casale and Danielle Simmons also participated in the studies, which were funded by the National Institutes of Health.

Subtle Signs Can Help Predict Huntington's Disease Early

Subtle signs can help doctors predict that a person will develop Huntington's disease in the next few years, according to a study published in the May 15, 2007, issue of Neurology®, the scientific journal of the American Academy of Neurology. Huntington's disease is a genetic disorder that affects movement, thinking, and some aspects of personality. There is no treatment or cure for the disease.

"These results will help us understand how and who will develop Huntington's, which is important information as potential treatments are developed," said study author Jane S. Paulsen, PhD, of the University of Iowa Roy J. and Lucille A. Carver College of Medicine in Iowa City. "Ideally, treatments will target at-risk people at or before the earliest stages of the disease, before they have any problems with thinking or movement."

The study involved 218 people in North America, Europe and Australia considered at risk for Huntington's disease because they had at least one parent with the disease. If a parent has the disease, there is a 50-percent chance that the child will develop the disease.

The participants were healthy at the beginning of the study, with normal scores on movement tests or minimal signs of movement problems. They were then followed for up to 4.5 years. Those with minimal motor problems at the beginning of the study were nearly five times more likely to be diagnosed with the disease a year and a half later than those who had no movement problems initially. They were 3.5 times more likely to be diagnosed with the disease after three years.

Researchers also tested cognitive abilities. For a verbal fluency test, they were given a letter of the alphabet and 60 seconds to say as many words as they could starting with that letter. They were also tested on how quickly they could combine thinking and movement, or "psychomotor speed," with a memory and writing task. Those who performed worse on the psychomotor test than on the verbal fluency test were twice as likely to be diagnosed with Huntington's disease a year and a half later than those whose tests scores were equivalent.

The study was supported by grants from the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, the Roy J. and Lucille Carver Trust, the Howard Hughes Medical Institute, the High Q Foundation, the Huntington's Disease Society of America, the Huntington's Society of Canada, and the Hereditary Disease Foundation.

Scientists Encourage Cells To Make A Meal Of Huntington's Disease

Scientists have developed a novel strategy for tackling neurodegenerative diseases such as Huntington's disease: encouraging an individual's own cells to "eat" the malformed proteins that lead to the disease.

Huntington's disease is one of a number of degenerative diseases marked by clumps of malformed protein in brain cells. Symptoms include abnormal movements, psychiatric disturbances like depression and a form of dementia. The gene responsible for the disease was discovered in 1993, leading to a better understanding of the condition and to improved predictive genetic testing, but it has yet to lead to any treatments that slow the neurodegeneration in Huntington's patients.

Professor David Rubinsztein, a Wellcome Trust Senior Clinical Fellow at the University of Cambridge, has been studying the molecular biology underlying Huntington's and other neurodegenerative diseases. Huntington's occurs when a protein known as huntingtin builds up in the brain cells of patients, mainly in neurons in the basal ganglia and in the cerebral cortex. Normally, cells dispose of or recycle their waste material, including unwanted or mis-folded proteins, through a process known as autophagy, or "self-eating".

"We have shown that stimulating autophagy in the cells — in other words, encouraging the cells to eat the malformed huntingtin proteins — can be an effective way of preventing them from building up," says Professor Rubinsztein. "This appears to stall the onset of Huntington's-like symptoms in fruit fly and mice, and we hope it will do the same in humans."

Autophagy can be induced in mouse and fly models by administering the drug rapamycin, an antibiotic used as an immunosuppressant for transplant patients. However, administered over the long term, the drug has some side effects and Rubinsztein and colleagues are aiming to find safer ways of inducing autophagy long term.

Now, Professor Rubinsztein, together with Professor Stuart Schreiber's lab at the Broad Institute of Harvard/MIT, Boston in the US, and Dr Cahir O'Kane's group in the Department of Genetics at the University of Cambridge have found a way of identifying novel "small molecules" capable of inducing autophagy. The research is published today in the journal Nature Chemical Biology.

The screening process involves identifying small molecules that enhance or suppress the ability of rapamycin to slow the growth of yeast, though the selected molecules have no effects on yeast growth by themselves. Yeast is a single-celled organism and therefore less complex to study for initial screening purposes.

Three of the molecules that enhanced the growth-suppressing effects of rapamycin in yeast were also found to induce autophagy by themselves in mammalian cells independent of the action of rapamycin. These molecules enhanced the ability of the cells to dispose of mutant huntingtin in cell and fruit fly models and protect against its toxic effects.

"These compounds appear to be promising candidates for drug development," says Professor Rubinsztein. "However, even if one of the candidates does prove to be successful, it will be a number of years off becoming available as a treatment. In order for such drugs to be useful candidates in humans, we will need to be able to get them into right places in the right concentrations, and with minimal toxicity. These are some of the issues we need to look at now."

Proteasome Activator Enhances Survival Of Huntington's Disease Neuronal Model Cells

 To function, each living cell needs both to build new and to degrade old or damaged proteins. To accomplish that, a number of intracellular systems work in concert to keep the cell healthy and from clogging up with damaged proteins. When proteins or peptides mutate, they can present major problems to the clearing up of the intracellular environment. In Huntington's disease (HD) the disease provoking mutation in the huntingtin gene eventually causes the cell to build up intranuclear and cellular inclusions of protein-aggregates, made up primarily of huntingtin. One cellular organelle with a central role of clearing such protein build up in the cell is the ubiquitin proteasome system (UPS).

In Huntington's disease (HD) brains and other tissues, UPS activity is inhibited and intraneuronal nuclear protein aggregates of mutant huntingtin in HD brains indicate dysfunction of the UPS. From these results, we hypothesized that enhancing UPS function would improve catalytic degradation of abnormal proteins in HD. We first genetically engineered proteasome activators involved in either non-ubiquitinated protein degradation pathways (PA28ƒ×) or subunits of PA700, the 26S proteasome ubiquitinated pathway (S5a) into transducible lentiviral vectors. To address the therapeutic hypothesis experimentally, we transduced UPS subunits into HD skin fibroblasts or HD mutant protein expressing striatum-derived neurons. We determined how this intervention altered cell survival after exposure to toxins known to simulate pathological mechanisms in HD.

The manuscript shows that cellular changes due to expression of huntingtin protein with longer CAG repeats can reduce the ubiquitin proteasome system (UPS) function in Huntington¡¦s disease cells. Following compromise of the UPS, the overexpression of proteasome activator PA28 can specifically recover proteasome function and improve cell viability in both HD model and patient cells.

These remarkable results demonstrate for the first time that it is possible to intervene therapeutically in the proteolytic pathways and organelles that participate in the specific degradation of misfolded and abnormal proteins.

Citation: Seo H, Sonntag K-C, Kim W, Cattaneo E, Isacson O (2007) Proteasome Activator Enhances Survival of Huntington¡¦s Disease Neuronal Model Cells. PLoS ONE 2(2): e238. doi:10.1371/journal.pone.0000238 (http://dx.doi.org/10.1371/journal.pone.0000238 )

Researchers Discover Zip Codes For Protein

McMaster scientists are very close to defining small molecule drugs that should be able to redirect the huntingtin protein from accumulating in the wrong place within brain cells, which could potentially translate to a therapy for Huntington's Disease (HD).

There is currently no way to stop or reverse the progression of Huntington's Disease, which affects one in 10,000 Americans. It is a progressive, and eventually fatal, genetic neurological disease.

Associate professor Ray Truant's lab has discovered molecular 'zip codes' or protein sequences in the huntingtin protein that dictate where it goes to within a brain cell.

"We have shown that the mutant huntingtin protein is mis-localized in brain cells in Huntington's Disease, because it is being improperly signaled, or instructed where to go in the cell," said Truant, of the Department of Biochemistry and Biomedical Sciences.

"In particular, Huntingtin is accumulating at the heart of the cell, the nucleus, where it shouldn't be. This is causing the brain cells to not function properly, and eventually die."

Truant and his university colleagues have received a $260,000 research operating grant from the American-based High Q Foundation. The grant will fund research using the technology of McMaster's new Biophotonics Facility and the use of laser microscopy in living brain cells.

It will also use the McMaster High Throughput Screening Facility to screen for new drugs that can affect how huntingtin is signalled.

"This class of small molecule drugs we are now working with has been proven recently to be a very successful class of drugs for different diseases, but not yet in HD," said Truant.

This new type of research is called Chemical Biology and is the focus of a new graduate degree program at McMaster University. The federal Canada Foundation for Innovation recently announced a $8 million grant towards a new Centre of Microbial Chemical Biology at McMaster.

Link Between Huntington's And Abnormal Cholesterol Levels Discovered In Brain

Mayo Clinic researchers have discovered a protein interaction that may explain how the deadly Huntington's disease affects the brain. The findings, published in and featured on the cover of the current issue of Human Molecular Genetics, show how the mutated Huntington's protein interacts with another protein to cause dramatic accumulation of cholesterol in the brain.

"Cholesterol is essential for promoting the connection network among brain cells and in maintaining their membrane integrity. Both the level of cholesterol and its delivery to the proper locations in the cell are essential for the survival of neurons," explains Mayo Clinic molecular biologist Cynthia McMurrary, Ph.D.

"Our discovery that the mutant Huntington's disease protein derails the cholesterol delivery system and causes cholesterol accumulation in neurons provides us with key results and solid clues to the mechanism of this disease," says Dr. McMurray. "Fully understanding the mechanism of toxicity is the key to developing treatments."

Huntington's disease — sometimes called Huntington's chorea or St. Vitus' dance — is a progressive, degenerative condition that causes nerve cells in the brain to waste away. Symptoms include uncontrolled movements, emotional disturbances and mental deterioration.

The mutant protein of Huntington's attacks the railroad system of brain cells and impairs transport of essential materials required for neurons to function. When this transportation system goes awry in the parts of the brain affected in Huntington's disease, motor skills, cognitive skills and even speech can be affected. A person cannot move without shaking, and physical control gradually deteriorates, often with accompanying personality changes, depression and increased risk of suicide. Those who have Huntington's commonly die from complications of the disease, such as falls or infections.

Approximately 30,000 Americans have Huntington's disease. Another 150,000 carry the gene and have a 50 percent risk of passing it on to their children. The disease is easily diagnosed by a blood test, but symptoms usually don't appear until middle age.

Their findings, say the researchers, provide the first direct link between the Huntington's protein and the protein that controls capture and trafficking inside the cell. Their research suggests a possible means by which Huntington's disease functions.

Because no one knows how the disease is incurred or spreads, this new information is critical and establishes a clear path for investigations to move forward.

The Mayo researchers observed the abnormal accumulation of cholesterol in cultured neuronal cells in the laboratory and in the brains of animal models. They found that this happens only when the mutant Huntington's protein is expressed together with the molecule, caveolin-1. Caveolin-1 is the major structural protein of small vesicles called caveolae, which capture cholesterol and move it in and out of the neuronal membranes. When the researchers "knocked out" expression of caveolin, the neurons expressing mutant Huntington's protein stopped accumulating cholesterol.

Others team members include key researcher Eugenia Trushina, Ph.D.; together with Raman Deep Singh, Ph.D.; Roy B. Dyer, Ph.D.; Sheng Cao, M.D.; Vijay H. Shah, M.D.; and Richard E. Pagano, Ph.D.; all of Mayo Clinic; and Robert G. Parton, Ph.D., of the University of Queensland. The research was supported by the Hereditary Disease Foundation, the National Institutes of Health, the American Heart Association and Mayo Clinic.

Test Reveals Effectiveness Of Potential Huntington's Disease Drugs

A test using cultured cells provides an effective way to screen drugs against Huntington's disease and shows that two compounds — memantine and riluzole — are most effective at keeping cells alive under conditions that mimic the disorder, UT Southwestern Medical Center researchers report.

"These drugs have been tested in a variety of Huntington's disease models and some HD human trials and results are very difficult to interpret," said Dr. Ilya Bezprozvanny, associate professor of physiology and senior author of the study, available online and published in today's issue of Neuroscience Letters. "For some of these drugs conflicting results were obtained by different research groups, but it is impossible to figure out where the differences came from because studies were not conducted in parallel.

"We systematically and quantititatively tested the clinically relevant drugs side-by-side in the same HD model. That has never been done before," said Dr. Bezprozvanny.

Huntington's disease is a fatal genetic disorder, manifesting in adulthood, in which certain brain cells die. The disease results in uncontrolled movements, emotional disturbance and loss of mental ability. The offspring of a person with Huntington's have a 50 percent chance of inheriting it.

More than 250,000 people in the United States have the disorder or are at risk for it. There is no cure, but several drugs are used or are being tested to relieve symptoms or slow Huntington's progression.

The disease affects a part of the brain called the striatum, which is involved in the control of movement and of "executive function," or planning and abstract thinking. It primarily attacks nerve cells called striatal medium spiny neurons, the main component of the striatum.

Dr. Bezprozvanny's group previously demonstrated that Huntington's striatal neurons are oversensitive to glutamate, a compound that nerve cells use to communicate with each other.

In the latest UT Southwestern study, the researchers cultured striatal spiny neurons from the brains of mice genetically engineered to express the mutant human Huntington gene. As predicted, glutamate killed the Huntington's neurons, but the scientists also tested five clinically relevant glutamate inhibitors to assess their protective ability.

Folic acid has been suggested as a treatment for people with Huntington's because it interacts with homocysteine, a compound that makes nerve cells more vulnerable to glutamate. Gabapentin and lamotrigine, both glutamate inhibitors, are used in epilepsy treatment and as a mood stabilizer, respectively. These three compounds did not significantly protect the cultured cells.

However, a drug called memantine, which is used to treat Alzheimer's disease, and riluzole, used in amyotrophic lateral sclerosis, did protect the cells. Memantine demonstrated a stronger effect in the study. Memantine has also shown evidence of retarding the progression of Huntington's in people, while riluzole has helped relieve some symptoms.

"Our results provide the first systematic comparison of various clinically relevant glutamate pathway inhibitors for HD treatment and indicate that memantine holds the most promise based on its in vitro efficacy," Dr. Bezprozvanny said. "Whole animal studies of memantine in an HD mouse model will be required to validate these findings."

Other UT Southwestern researchers involved in the study were Drs. Jun Wu, research associate in physiology, and Tie-Shan Tang, instructor in physiology.

The work was supported by the Robert A. Welch Foundation, the High Q Foundation and the National Institute for Neurological Diseases and Stroke.

Metabolic Disorder Underlies Huntington's Disease

A metabolic disorder underlies the brain effects found in those with Huntington's disease, researchers report in an advance article publishing online October 19, 2006. The article will appear in the November 2006 issue of the journal Cell Metabolism, published by Cell Press.

Their new evidence ties a metabolic defect to the loss of neurons in the striatum, the brain's "movement control" region. That neurodegeneration leads to the uncontrollable "dance-like" movements characteristic of the fatal, genetic disorder.

The findings may help to explain other symptoms of the disease, including weight loss, and could point to new avenues for therapy, according to the researchers.

"Huntington's has been thought of primarily as a neurological disease," said Albert R. La Spada of the University of Washington, Seattle. "Our findings underscore the fact that the condition includes other, underrecognized aspects."

The findings in Huntington's disease further highlight the possibility that other neurological conditions might also have a strong metabolic component, La Spada added.

Huntington's is relentlessly progressive, the researchers said, as patients succumb to the disease 10 to 25 years after its onset. The disease is caused by a genetic defect in which a repetitive sequence of DNA in the "huntingtin" (htt) gene gets expanded to encode an abnormally elongated protein.

Although the mutant htt protein is widely present, only certain populations of neurons degenerate and only a subset of other cell types are affected, they said. And exactly how the htt protein causes disease has remained uncertain.

The researchers made their current discovery after stumbling onto evidence that mice with Huntington's disease suffer extremely low body temperatures that worsen as the disease progresses.

"These mice have been around for at least a decade," La Spada said. "They have been the subjects of dozens, if not hundreds, of studies, but no one had checked one of their most basic vital signs.

"When you do, you find that the mice have a dramatic abnormality in temperature–which is normally tightly regulated."

Early on, the animals' temperature registered one or two degrees below normal, La Spada said. As their condition worsened, body temperatures fell substantially, he added, sometimes below 30°C. Like humans, the normal body temperature of mice is about 37°C.

To trace the causes of the animals' hypothermia, the researchers first looked to the brain region that controls body temperature. The animals brains, however, appeared to register and respond to cold normally.

The problem, they found, lay instead in fat cells known as brown adipose tissue (BAT). In rodents, BAT is the primary tissue that controls body temperature. When the brain signals that the body is cold, the gene called PGC-1á increases production of a protein in BAT that leads the cellular powerhouses known as mitochondria to generate heat instead of energy.

In the BAT of hypothermic Huntington's mice, PGC-1á levels rose but failed to elicit the other events required to maintain normal body temperature, they found.

The link to mitochondria-regulating PGC-1á led the team back to the brain, and specifically to the striatum. That brain region is most affected in Huntington's disease and is particularly sensitive to mitochondrial dysfunction.

The researchers found that tissue taken from striatums of Huntington's disease patients and mice showed reduced activity of genes controlled by PGC-1á. They further found reduced mitochondrial function in the brains of Huntington's mice.

The findings suggest a link between two theories to explain Huntington's disease, the researchers said.

The earlier finding that the striatum is particularly sensitive to mitochondrial dysfunction suggested that the cellular powerhouses might play a role in the disease. Other evidence suggested that mutant htt might interfere with "transcription factors" that control gene activity.

"PGC-1á transcription interference may provide a link between transcription dysregulation and mitochondrial dysfunction in Huntington's disease," the researchers said. "More importantly, our study underscores an emerging role for metabolic and mitochondrial abnormalities in neurodegenerative disease."

As metabolic function generally diminishes in older people, such a connection might explain why many neurodegenerative diseases–such as Lou Gehrig's, Alzheimer's, and Parkinson's diseases, for example–tend to emerge and worsen with age, La Spada said.

The researchers include Patrick Weydt, Victor V. Pineda, Anne E. Torrence, Randell T. Libby, Terrence F. Satterfield, Merle L. Gilbert, Gregory J. Morton, Theodor K. Bammler, Richard P. Beyer, Courtney N. Easley, Annette C. Smith, Serge Luquet, Ian R. Sweet, Michael W. Schwartz, and Albert R. La Spada of University of Washington in Seattle; Eduardo R. Lazarowski of University of North Carolina in Chapel Hill; Andrew D. Strand of Fred Hutchinson Cancer Research Center in Seattle; and Libin Cui and Dimitri Krainc of Massachusetts General Hospital and Harvard Medical School in Boston. This work was supported by funding from Hereditary Disease Foundation, High Q, and grants from the NIH (DK17047 and DK063986 to I.R.S.; NS050352 to D.K.). A.R.L. is the recipient of a Paul Beeson Physician Faculty Scholar in Aging Research award from the American Foundation for Aging Research (AFAR), and V.V.P. is a NIH Genetics of Aging postdoctoral fellow (AG00057).

Weydt et al.: "Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1á in Huntington's disease neurodegeneration." Publishing in Cell Metabolism, Volume 4, Issue 5, November 2006.