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Mitochondrial mutations may underlie late-onset AD
Newsdesk
Late-onset Alzheimer’s disease (AD) may be caused by a mutation in the mitochondrial DNA (mtDNA). “We have discovered that somatic mutations in the mtDNA are a common feature of late-onset AD brains, but are uncommon in control brains”, says investigator Douglas Wallace (University of California, Irvine, CA, USA). Mutations in mitochondrial proteins reduce energy production, which increases oxidative stress and instigates cell death. Although genetic mutations are thought to cause earlyonset AD, the cause of late-onset AD is not clear. Various mitochondrial mutations have been found in AD cases, leading Wallace and colleagues to examine AD brains for disease-causing mutations (Proc Natl Acad Sci USA 2004; 101: 10726–31). They studied frontal cortex brain samples obtained at autopsy from people who died age 59–94 years. 23 of the samples had been pathologically confirmed as being from people with
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Mitochondria: DNA mutation may be cause
AD and these were age-matched to 40 control samples for comparison. The mtDNA control region was sequenced. The researchers studied of 250 AD and 235 control clones and found 63% more mitochondrial control-region mutations in the brains of people who had AD. In DNA from people older than 80 years of age, there were 130% more mutations in the AD than the control samples. Three mutations—
Bill Longcore/Science Photo Library
Mitochondrial mutations may underlie late-onset AD 414T→G, 414T→C, and 477T→C— were specific to the AD samples. 65% of the AD brains had the 414T→G mutation. Mutations in the AD brains differed according to age; samples taken from people younger than 83 years had large numbers of the same mutations but in samples taken from older people the mutations were different. The authors suggest that differences in the types of mutations may reflect the age at which they developed. “Mitochondrial production of reactive oxygen species and the associated accumulation of somatic mtDNA control-region mutations in AD is the cause of AD-related dementia”, says Wallace. However, Shigeo Ohta (Nippon Medical School, Kawasaki, Japan) believes “mt DNA mutation is one of the causes of the mitochondrial dysfunction in AD”. Even so, Ohta predicts this research “will have some important clinical implications, especially in the prevention of AD”. Gillian Carmichael
K-channel function changes in acquired epilepsies Downregulation of K channels located in neuronal dendrites in the hippocampus could contribute to chronic temporal-lobe epilepsy. “This is the first demonstration of an acquired channelopathy in epilepsy”, says Christophe Bernard (INSERM U29, Marseille Cédex, France), the lead investigator of the new study. “Channel function can be altered persistently or transiently via a multitude of intracellular mechanisms. Surprisingly little is known about these types of modifications in acquired diseases, which are considerably more frequent than inherited ones”, he says. K channels, which allow positively charged potassium ions to flow out of the cell, are key regulators of neuronal excitability. Action potentials are generated in the soma and travel along the axon to the presynaptic terminals. Importantly, however, action potentials also back-propagate along the dendrites; this “echo” signal tells the synapses that the neuron has fired an action potential. The
Neurology Vol 3 September 2004
amplitude of back-propagating action potentials is substantially larger than the signals generated by incoming synaptic signals. To prevent dendrites becoming saturated with such a large signal, explains Bernard, there are many more K channels located in the distal portions of the dendrites than in the more proximal ones. As a result, the amplitude of the back-propagating action potential decreases the deeper it penetrates into the dendrites. Bernard’s team hypothesised that changes in K channel density in dendrites could contribute to temporal-lobe epilepsy. The researchers gave pilocarpine, which activates acetylcholine receptors, to healthy rats to induce prolonged seizures that killed many neurons in the hippocampus. A few weeks later the animals developed spontaneous seizures similar to those seen in chronic temporal-lobe epilepsy. They used a combination of electrophysiological and molecular biology techniques to show that the
http://neurology.thelancet.com
increased dendritic excitability was caused by a decreased availability of dendritic K channels (Science 2004; 305: 532–35). “The molecular mechanism underlying this acquired change is most probably a transcriptional downregulation of K channels (less channels are made), in concert with a posttranscriptional modification of remaining channels by extracellularregulated kinase (ERK)”, says Bernard. ERK phosphorylates channels, making them less active. Bernard’s team was able to block the ERK pathway pharmacologically, which brought dendritic excitability back up to control levels. “Drugs specifically targeting the phosphorylation sites of K channels might prove to be efficient anticonvulsants”, says Bernard. One drug, U0126, exists but is broad spectrum. “We intend to pursue the study on human tissue excised from patients with intractable epilepsy”. William Taylor
513
For personal use. Only reproduce with permission from Elsevier Ltd.
Late-onset Alzheimer’s disease (AD) may be caused by a mutation in the mitochondrial DNA (mtDNA). “We have discovered that somatic mutations in the mtDNA are a common feature of late-onset AD brains, but are uncommon in control brains”, says investigator Douglas Wallace (University of California, Irvine, CA, USA). Mutations in mitochondrial proteins reduce energy production, which increases oxidative stress and instigates cell death. Although genetic mutations are thought to cause earlyonset AD, the cause of late-onset AD is not clear. Various mitochondrial mutations have been found in AD cases, leading Wallace and colleagues to examine AD brains for disease-causing mutations (Proc Natl Acad Sci USA 2004; 101: 10726–31). They studied frontal cortex brain samples obtained at autopsy from people who died age 59–94 years. 23 of the samples had been pathologically confirmed as being from people with
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Mitochondria: DNA mutation may be cause
AD and these were age-matched to 40 control samples for comparison. The mtDNA control region was sequenced. The researchers studied of 250 AD and 235 control clones and found 63% more mitochondrial control-region mutations in the brains of people who had AD. In DNA from people older than 80 years of age, there were 130% more mutations in the AD than the control samples. Three mutations—
Bill Longcore/Science Photo Library
Mitochondrial mutations may underlie late-onset AD 414T→G, 414T→C, and 477T→C— were specific to the AD samples. 65% of the AD brains had the 414T→G mutation. Mutations in the AD brains differed according to age; samples taken from people younger than 83 years had large numbers of the same mutations but in samples taken from older people the mutations were different. The authors suggest that differences in the types of mutations may reflect the age at which they developed. “Mitochondrial production of reactive oxygen species and the associated accumulation of somatic mtDNA control-region mutations in AD is the cause of AD-related dementia”, says Wallace. However, Shigeo Ohta (Nippon Medical School, Kawasaki, Japan) believes “mt DNA mutation is one of the causes of the mitochondrial dysfunction in AD”. Even so, Ohta predicts this research “will have some important clinical implications, especially in the prevention of AD”. Gillian Carmichael
K-channel function changes in acquired epilepsies Downregulation of K channels located in neuronal dendrites in the hippocampus could contribute to chronic temporal-lobe epilepsy. “This is the first demonstration of an acquired channelopathy in epilepsy”, says Christophe Bernard (INSERM U29, Marseille Cédex, France), the lead investigator of the new study. “Channel function can be altered persistently or transiently via a multitude of intracellular mechanisms. Surprisingly little is known about these types of modifications in acquired diseases, which are considerably more frequent than inherited ones”, he says. K channels, which allow positively charged potassium ions to flow out of the cell, are key regulators of neuronal excitability. Action potentials are generated in the soma and travel along the axon to the presynaptic terminals. Importantly, however, action potentials also back-propagate along the dendrites; this “echo” signal tells the synapses that the neuron has fired an action potential. The
Neurology Vol 3 September 2004
amplitude of back-propagating action potentials is substantially larger than the signals generated by incoming synaptic signals. To prevent dendrites becoming saturated with such a large signal, explains Bernard, there are many more K channels located in the distal portions of the dendrites than in the more proximal ones. As a result, the amplitude of the back-propagating action potential decreases the deeper it penetrates into the dendrites. Bernard’s team hypothesised that changes in K channel density in dendrites could contribute to temporal-lobe epilepsy. The researchers gave pilocarpine, which activates acetylcholine receptors, to healthy rats to induce prolonged seizures that killed many neurons in the hippocampus. A few weeks later the animals developed spontaneous seizures similar to those seen in chronic temporal-lobe epilepsy. They used a combination of electrophysiological and molecular biology techniques to show that the
http://neurology.thelancet.com
increased dendritic excitability was caused by a decreased availability of dendritic K channels (Science 2004; 305: 532–35). “The molecular mechanism underlying this acquired change is most probably a transcriptional downregulation of K channels (less channels are made), in concert with a posttranscriptional modification of remaining channels by extracellularregulated kinase (ERK)”, says Bernard. ERK phosphorylates channels, making them less active. Bernard’s team was able to block the ERK pathway pharmacologically, which brought dendritic excitability back up to control levels. “Drugs specifically targeting the phosphorylation sites of K channels might prove to be efficient anticonvulsants”, says Bernard. One drug, U0126, exists but is broad spectrum. “We intend to pursue the study on human tissue excised from patients with intractable epilepsy”. William Taylor
513
For personal use. Only reproduce with permission from Elsevier Ltd.