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Huntingtin protein causes mitochondrial calcium abnormalities
SCIENCE AND MEDICINE
Huntingtin protein causes mitochondrial calcium abnormalities
T
he discovery of the genetic stutter that causes Huntington’s disease in 1993 left researchers with a mystery. How does the overly repeated DNA triplet that codes for glutamine, thus producing a malformed version of the protein huntingtin, actually lead to damage of nerve cells in the brain? A new study by a team of US and Canadian scientists suggests that the expanded polyglutamine sequence in the mutant huntingtin protein causes cell damage and or death by its effects on mitochondrial membranes in those cells. The finding may shed light on the pathogenesis of several similar neurodegenerative diseases, such as the spinocerebellar ataxias. The research team—consisting of investigators from Emory University (GA, USA), the University of British Columbia (Canada), and Duke University (NC, USA)—analysed mitochrondria taken from lymphoblasts. Mitochondria of patients with Huntington’s disease had reduced resting membrane potentials and
reduced calcium retention capacity than mitochondria from healthy patients. Similar patterns were observed in brain mitochondria from mice genetically modified to express the mutant huntingtin— and the patterns preceded the appearance of Huntington-like signs by several months (Nat Neurosci, published online July 1, 2002; DOI: 10.1038/nn884). The investigators then showed that the abnormal mitochondrial calcium responses found in patients and transgenic mice could be reproduced by exposing normal lymphocyte mitochondria to proteins with pathologically long polyglutamine tracts. While reduced membrane potentials and calcium imbalances would theoretically affect all mitochondria in the body, the brain is especially vulnerable, says senior researcher Tim Greenamyre (Emory University School of Medicine), because it depends more than most organs on large amounts of ATP produced through cellular respiration for energy.
The mutant huntingtin protein may act by opening too many channels in the mitochondrial membranes, thus allowing ions such as calcium to leak through, says Elena Cattaneo (University of Milan, Italy), who is writing an accompanying commentary on the article to be published in the August issue of Nature Neuroscience. Those leaks may reduce the electrical gradients that are needed to drive the synthesis of ATP, Greenamyre says. Neither Greenamyre nor Cattaneo are sure why the symptoms of Huntington’s disease take so long to appear. “This is crucial and difficult to answer. Maybe there are subtle dysfunctions that accumulate over the years and that we cannot detect”, says Cattaneo. “One should consider also that the physiological defence mechanisms in an ‘old’ brain of about 30–35 years . . . are somehow very different from the defence mechanisms present at younger ages”, she adds. David Lawrence
Obesity prevention must start in childhood, says US heart association down the disease process and maybe prevent it completely.”
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Hold the ice cream
The new guidelines focus on practical interventions that physicians can “incorporate into different aspects of well child care”, says Williams. “The idea is to create a mindset, that when they’re concentrating on the child’s vaccinations, growth, and safety
Mental illness not an obstacle to health behaviour counselling A review of 90 000 patient records from US Veterans Administration (VA) medical centres revealed similar rates of nutrition and exercise counselling for obese and/or hypertensive individuals, regardless of whether such patients also have a mental illness. This contrasts with previous studies that suggest patients with mental health disorders may be vulnerable to receiving lower quality health care than people without such conditions (J Gen Intern Med 2002; 17: 1–5).
Anthony Blake Photo Library
romoting diet and lifestyle changes in childhood can reduce the risk of coronary heart disease “in individual children and the population at large”, reports the American Heart Association’s committee on atherosclerosis, hypertension, and obesity in the young (AHOY) in a scientific statement released this week (see www.americanheart.org). “Physicians tend to look at children running around and say, ‘oh, they’re healthy; there’s nothing wrong with them”, observes lead author and immediate past chair of the committee, Christine Williams (Columbia University’s Babies and Children’s Hospital, New York, NY, USA). “But many of these children have risk factors for heart disease and if you can get them on the right track when they’re little, then you can slow
P
things, they should look for heart health, too.” For example, for children as young as age 2 years, physicians should start emphasising a heart-healthy diet and regular exercise, according to the guidelines. Other strategies include measuring blood pressure during routine visits in children aged 3 years and older; using fasting plasma glucose testing for children at risk for type 2 diabetes; monitoring cholesterol of children in families with heart risk factors; obtaining a smoking history for children older than age 8 years; and providing age-specific antismoking messages (Circulation 2002; 106: 143–60). Rates of obesity have doubled among US young people in the past 20 years, notes Williams, and a recent study suggests that excess body weight costs the US health-care system an estimated US$31 billion to treat overweight and obese people who develop heart disease. “We must act now or overweight young people could be at risk of developing heart disease at an earlier age than their parents’ generation”, warns Williams. Marilynn Larkin
62
THE LANCET • Vol 360 • July 6, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Huntingtin protein causes mitochondrial calcium abnormalities
T
he discovery of the genetic stutter that causes Huntington’s disease in 1993 left researchers with a mystery. How does the overly repeated DNA triplet that codes for glutamine, thus producing a malformed version of the protein huntingtin, actually lead to damage of nerve cells in the brain? A new study by a team of US and Canadian scientists suggests that the expanded polyglutamine sequence in the mutant huntingtin protein causes cell damage and or death by its effects on mitochondrial membranes in those cells. The finding may shed light on the pathogenesis of several similar neurodegenerative diseases, such as the spinocerebellar ataxias. The research team—consisting of investigators from Emory University (GA, USA), the University of British Columbia (Canada), and Duke University (NC, USA)—analysed mitochrondria taken from lymphoblasts. Mitochondria of patients with Huntington’s disease had reduced resting membrane potentials and
reduced calcium retention capacity than mitochondria from healthy patients. Similar patterns were observed in brain mitochondria from mice genetically modified to express the mutant huntingtin— and the patterns preceded the appearance of Huntington-like signs by several months (Nat Neurosci, published online July 1, 2002; DOI: 10.1038/nn884). The investigators then showed that the abnormal mitochondrial calcium responses found in patients and transgenic mice could be reproduced by exposing normal lymphocyte mitochondria to proteins with pathologically long polyglutamine tracts. While reduced membrane potentials and calcium imbalances would theoretically affect all mitochondria in the body, the brain is especially vulnerable, says senior researcher Tim Greenamyre (Emory University School of Medicine), because it depends more than most organs on large amounts of ATP produced through cellular respiration for energy.
The mutant huntingtin protein may act by opening too many channels in the mitochondrial membranes, thus allowing ions such as calcium to leak through, says Elena Cattaneo (University of Milan, Italy), who is writing an accompanying commentary on the article to be published in the August issue of Nature Neuroscience. Those leaks may reduce the electrical gradients that are needed to drive the synthesis of ATP, Greenamyre says. Neither Greenamyre nor Cattaneo are sure why the symptoms of Huntington’s disease take so long to appear. “This is crucial and difficult to answer. Maybe there are subtle dysfunctions that accumulate over the years and that we cannot detect”, says Cattaneo. “One should consider also that the physiological defence mechanisms in an ‘old’ brain of about 30–35 years . . . are somehow very different from the defence mechanisms present at younger ages”, she adds. David Lawrence
Obesity prevention must start in childhood, says US heart association down the disease process and maybe prevent it completely.”
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Hold the ice cream
The new guidelines focus on practical interventions that physicians can “incorporate into different aspects of well child care”, says Williams. “The idea is to create a mindset, that when they’re concentrating on the child’s vaccinations, growth, and safety
Mental illness not an obstacle to health behaviour counselling A review of 90 000 patient records from US Veterans Administration (VA) medical centres revealed similar rates of nutrition and exercise counselling for obese and/or hypertensive individuals, regardless of whether such patients also have a mental illness. This contrasts with previous studies that suggest patients with mental health disorders may be vulnerable to receiving lower quality health care than people without such conditions (J Gen Intern Med 2002; 17: 1–5).
Anthony Blake Photo Library
romoting diet and lifestyle changes in childhood can reduce the risk of coronary heart disease “in individual children and the population at large”, reports the American Heart Association’s committee on atherosclerosis, hypertension, and obesity in the young (AHOY) in a scientific statement released this week (see www.americanheart.org). “Physicians tend to look at children running around and say, ‘oh, they’re healthy; there’s nothing wrong with them”, observes lead author and immediate past chair of the committee, Christine Williams (Columbia University’s Babies and Children’s Hospital, New York, NY, USA). “But many of these children have risk factors for heart disease and if you can get them on the right track when they’re little, then you can slow
P
things, they should look for heart health, too.” For example, for children as young as age 2 years, physicians should start emphasising a heart-healthy diet and regular exercise, according to the guidelines. Other strategies include measuring blood pressure during routine visits in children aged 3 years and older; using fasting plasma glucose testing for children at risk for type 2 diabetes; monitoring cholesterol of children in families with heart risk factors; obtaining a smoking history for children older than age 8 years; and providing age-specific antismoking messages (Circulation 2002; 106: 143–60). Rates of obesity have doubled among US young people in the past 20 years, notes Williams, and a recent study suggests that excess body weight costs the US health-care system an estimated US$31 billion to treat overweight and obese people who develop heart disease. “We must act now or overweight young people could be at risk of developing heart disease at an earlier age than their parents’ generation”, warns Williams. Marilynn Larkin
62
THE LANCET • Vol 360 • July 6, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.