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Molecular insights into letting sleeping dogs lie
Home-town memories overturn long-standing view of hippocampus ontrary to a widely held view among neuroscientists, the hippocampus is not the long-term storage site for spatial maps and other distant memories, report researchers at the University of California, San Diego (La Jolla, CA, USA). Larry Squire and Edmond Teng asked a severely amnesiac 76-yearold patient whether he could recall the layout of the streets and landmarks of his home town, which he had not visited in more than 50 years. They compared his memory of the neighbourhood with that of 5 former schoolmates who had lived in the town for a similar period of time before moving away. Although the patient had complete bilateral damage to the hippocampus and other memory components after an episode of herpes simplex encephalitis in 1992, he could remember his home town as well as his former schoolmates (Nature 1999; 400: 675-77).
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“When you have this huge lesion and get a finding of normal performance, it’s really quite compelling”, says Squire. But, he adds, the patient has no memory of his current neigh-
bourhood, where he moved after onset of the amnesia, which suggests that the hippocampus is involved in new memory formation. A report from the University Bordeaux I in Talence, France, lends support to the theory. By studying
regional metabolic activity in the brains of mice at different times after learning a new task, Bruno Bontempi and co-workers showed that the hippocampus is indeed involved in the acquisition of new spatial memories and recall of recently acquired ones—mainly through interactions with the neocortex. But after several weeks, there is a gradual reorganisation of neuronal activity, hippocampal involvement fades, and long-term memories seem eventually to settle into cortical areas (Nature 1999; 400: 671-75). The findings “fit nicely” with the intactness of remote memory, comments Squire, and confirm that the “job” of the hippocampus is to form new memories, essentially by capturing “the moment itself, in time and space, and holding it all together” for subsequent processing. Marilynn Larkin
Gene behind Tangier disease may help reveal HDL’s secrets
B
y finding the gene responsible for a rare genetic disorder, scientists may have also helped begin to solve one of the remaining mysteries underlying atherosclerosis and cholesterol metabolism. This month, three separate groups report finding the gene which is mutated in Tangier disease (TD), a rare recessive disease characterised by orange tonsils, peripheral neuropathy, and a near-complete absence of HDLcholesterol. Although not all Tangier patients develop atherosclerosis, the absence of HDL and the accumulation of cholesterol in tissues in these patients led researchers to suspect that TD could help answer the question of
how HDL removes cholesterol from cells and thereby presumably helps to protect against atherosclerosis. The teams, led by Michael Hayden (University of British Columbia, Vancouver, Canada), Gerd Schmitz (University of Regensburg, Germany), and Gerd Assmann (Westfälische WilhelmsUniversität Münster, Germany), each discovered that ABC1, the ATP binding-cassette transporter 1 gene, is mutated in TD, and that the gene mediates the efflux of cholesterol from cells (Nat Genet 1999; 22: 336; 347; 352). Without a mechanism to remove cholesterol, cells may accumulate an excess. The researchers also found that
ABC1 is required in the manufacture of HDL. Without cholesterol, HDL particles fail to develop. Jack Oram (University of Washington, Seattle), who has studied cholesterol efflux and TD describes the finding as “one of the most important advances in lipoprotein metabolism and atherosclerosis ever”. In a commentary, Stephen Young and Christopher Fielding (University of California, San Francisco), agree that the discovery of ABC1 has “substantial implications for plasma lipoprotein metabolism”. The genemay also provide promising targets for drug interventions, they add. Larry Husten
Molecular insights into letting sleeping dogs lie he discovery of a gene for canine narcolepsy offers hope for patients with this disabling sleep disorder. Using positional cloning of the autosomal recessive canine narcolepsy gene, canarc-1, Emmanuel Mignot (Stanford University Medical School, Stanford, CA, USA) and colleagues pinpointed a mutation in the hypocretin (orexin) receptor 2 gene (Hcrtr2) as the cause of the disorder in dogs (Cell 1999; 98: 365–76). This finding, say the authors, also
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identifies hypocretins—a newly discovered family of neuropeptides—as important sleep-modulating neurotranssmitters. “We expect functional studies to show that central or peripheral administration of hypocretins will be potently wake-promoting and suppress REM sleep in control but not narcoleptic animals”, they comment. Human and canine narcolepsy are strikingly similar—with daytime
sleepiness, sleep fragmentation, and cataplexy—so abnormalities in the hypocretin neurotransmission system are likely to be involved in the human disorder. However, most cases of human narcolepsy are non-familial and are strongly HLA-associated, suggesting that an autoimmune mechanism or more complex neuroimmune reaction, may be involved in human narcolepsy. Dorothy Bonn
THE LANCET • Vol 354 • August 14, 1999
C
“When you have this huge lesion and get a finding of normal performance, it’s really quite compelling”, says Squire. But, he adds, the patient has no memory of his current neigh-
bourhood, where he moved after onset of the amnesia, which suggests that the hippocampus is involved in new memory formation. A report from the University Bordeaux I in Talence, France, lends support to the theory. By studying
regional metabolic activity in the brains of mice at different times after learning a new task, Bruno Bontempi and co-workers showed that the hippocampus is indeed involved in the acquisition of new spatial memories and recall of recently acquired ones—mainly through interactions with the neocortex. But after several weeks, there is a gradual reorganisation of neuronal activity, hippocampal involvement fades, and long-term memories seem eventually to settle into cortical areas (Nature 1999; 400: 671-75). The findings “fit nicely” with the intactness of remote memory, comments Squire, and confirm that the “job” of the hippocampus is to form new memories, essentially by capturing “the moment itself, in time and space, and holding it all together” for subsequent processing. Marilynn Larkin
Gene behind Tangier disease may help reveal HDL’s secrets
B
y finding the gene responsible for a rare genetic disorder, scientists may have also helped begin to solve one of the remaining mysteries underlying atherosclerosis and cholesterol metabolism. This month, three separate groups report finding the gene which is mutated in Tangier disease (TD), a rare recessive disease characterised by orange tonsils, peripheral neuropathy, and a near-complete absence of HDLcholesterol. Although not all Tangier patients develop atherosclerosis, the absence of HDL and the accumulation of cholesterol in tissues in these patients led researchers to suspect that TD could help answer the question of
how HDL removes cholesterol from cells and thereby presumably helps to protect against atherosclerosis. The teams, led by Michael Hayden (University of British Columbia, Vancouver, Canada), Gerd Schmitz (University of Regensburg, Germany), and Gerd Assmann (Westfälische WilhelmsUniversität Münster, Germany), each discovered that ABC1, the ATP binding-cassette transporter 1 gene, is mutated in TD, and that the gene mediates the efflux of cholesterol from cells (Nat Genet 1999; 22: 336; 347; 352). Without a mechanism to remove cholesterol, cells may accumulate an excess. The researchers also found that
ABC1 is required in the manufacture of HDL. Without cholesterol, HDL particles fail to develop. Jack Oram (University of Washington, Seattle), who has studied cholesterol efflux and TD describes the finding as “one of the most important advances in lipoprotein metabolism and atherosclerosis ever”. In a commentary, Stephen Young and Christopher Fielding (University of California, San Francisco), agree that the discovery of ABC1 has “substantial implications for plasma lipoprotein metabolism”. The genemay also provide promising targets for drug interventions, they add. Larry Husten
Molecular insights into letting sleeping dogs lie he discovery of a gene for canine narcolepsy offers hope for patients with this disabling sleep disorder. Using positional cloning of the autosomal recessive canine narcolepsy gene, canarc-1, Emmanuel Mignot (Stanford University Medical School, Stanford, CA, USA) and colleagues pinpointed a mutation in the hypocretin (orexin) receptor 2 gene (Hcrtr2) as the cause of the disorder in dogs (Cell 1999; 98: 365–76). This finding, say the authors, also
T
574
identifies hypocretins—a newly discovered family of neuropeptides—as important sleep-modulating neurotranssmitters. “We expect functional studies to show that central or peripheral administration of hypocretins will be potently wake-promoting and suppress REM sleep in control but not narcoleptic animals”, they comment. Human and canine narcolepsy are strikingly similar—with daytime
sleepiness, sleep fragmentation, and cataplexy—so abnormalities in the hypocretin neurotransmission system are likely to be involved in the human disorder. However, most cases of human narcolepsy are non-familial and are strongly HLA-associated, suggesting that an autoimmune mechanism or more complex neuroimmune reaction, may be involved in human narcolepsy. Dorothy Bonn
THE LANCET • Vol 354 • August 14, 1999