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Researchers from the Sleep andNeuroimaging Research Laboratory atHarvard Medical School (Boston, MA,USA) have shown that a good night’ssleep improves memory consolidationby inducing plastic changes in thehuman brain. Sleep is known to playan important part in memoryconsolidation and processing—babiesare thought to spend so much timeasleep because they are constantlytaking in new information that needsto be consolidated and stored asmemories in the brain. “The data
suggest that a night of sleepreorganises the representation of amemory within the human brain”,explains author Matthew Walker.
In their study, Walker and colleaguesused a finger-tapping test toinvestigate why sleep improves motormemory skills. 12 people were trainedon the test with their left hand. In onephase, subjects trained in themorning, and then retested on thetask after 12 h of being awake. In theother phase, subjects were trained inthe evening and retested after 12 h ofbeing asleep. To ensure that there wasno effect of circadian rhythm on theoutcome, both groups did bothversions of the retest in a counter-balanced order (Neuroscience 2005;133: 911–17).
Functional MRI during the retestingshowed that people who had beenasleep had better performanceaccuracy than those who had stayedawake. The researchers noted thatthose who had been asleep, comparedwith those who had been awake, hadincreased activity in several motorcentres (right primary motor cortexand left cerebellar cortex) and areas
involved in the construction ofmemory sequences (right prefrontallobe, right hippocampus, and rightventral striatum). In addition, activityin the parietal lobes was decreased inthose who had been asleep,suggesting that conscious monitoringof spatial movements was reduced.
“The changes in the fMRIrepresentation of the skill found byWalker and coauthors after a period ofsleep indicate that sleep promotesplastic changes in the brain’s neuronalnetworks mediating skilfulbehaviours”, comments Jan Born(University of Lubeck, Germany). “Thisfunction of sleep could be exploitedfor clinical purposes, for example inthe treatment of stroke patients to re-establish motor function.”
“Considering that westerncivilisation is consistently getting lessand less sleep each year, particularlyour school children, the importance ofunderstanding sleep-dependentlearning and brain plasticity is ofparamount importance”, concludesWalker.
Rebecca Love
Newsdesk
528 http://neurology.thelancet.com Vol 4 September 2005
A good night’s sleep is the key to remembering
p53 may have an important role inHuntington’s disease (HD) say USresearchers—a role that links nucleartranscription dysregulation and mito-chondrial abnormalities associatedwith the disorder (Neuron 2005; 47:29–41).
“Cell cultures expressing the mutanthuntingtin protein [mHtt] and thebrains of patients with HD have highconcentrations of p53”, explains AkiraSawa (Johns Hopkins UniversitySchool of Medicine, Baltimore, USA).“In addition, mitochondrial enzymeactivity is affected in HD, and thisorganelle is associated with p53’sactivities. We therefore thought thatp53 might be the link between the
disease’s nuclear and mitochondrialpathologies.”
Sawa’s team first confirmed thatnuclear p53 concentrations werenearly ten times higher in PC12 cellsexpressing mHtt compared with cellsexpressing wild-type Htt. They alsosaw high p53 concentrations in thebrains of transgenic mice expressing aform of mHtt and in patients with HDat postmortem, and always in thehallmark areas of the striatum andcerebral cortex. In all cases, p53 wasbound to the mHtt.
“In all the models we used, increasedp53 concentrations led to mitochon-drial dysfunction, the membranebecoming depolarised—another sign
of HD”, explains Sawa. “However, wewere able to prevent this withpifithrin-�, a p53 inhibitor. Indeed,this molecule or the use of RNAitechniques, blocked all the p53-induced problems in all ourexperiments.”
Specifically, p53 is thought todisrupt the activity of themitochondrial respiratory chaincomplexes II/III and IV. Thesecomplexes are impaired in the caudateand putamen in HD.
In further tests the researchersshowed that p53 mediated mHttcytotoxicity, tripling the death rate ofPC12 cells expressing the rogueprotein. However, it did not seem to
Possible role for p53 in Huntington’s disease
Sleeping like a baby: consolidation of memory during sleep improves performance
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Newsdesk
be involved in the formation of themHtt aggregates themselves. “Nodifferences were seen between theformation of aggregates in cultures ofp53-knockout cortical cells andnormal cells”, explains Sawa.
Further evidence of the involvementof p53 in HD came from experimentswith Drosophila models. In transgenicflies expressing an mHtt-type protein,photoreceptor neurons die. When theresearchers deleted the p53 gene, thisneurodegeneration was prevented. Inaddition, when the same gene wasdeleted in transgenic mice, theabnormal behaviour patterns normally
seen were prevented. “And again,pifithrin improved the behaviouralsymptoms of these HD-model mice”,says Sawa.
Although it is tempting to think thatblocking the action of p53 in patientswith HD might be of therapeuticvalue, this may not be so simple. p53 isinvolved in many vital cell functions,including apoptosis, and it isparticularly well known as a tumourinhibitor. Indeed, some statisticssuggest that patients with HD are lesslikely to develop cancer. Simplyblocking all p53 activity is thereforenot an option.
“However, it is conceivable thatinhibitory substances that blockspecific molecules downstream ofp53 in specific neuronal cellsmight be able to prevent the onsetand progress of HD”, says MimounAzzouz (Oxford Biomedica, Oxford,UK). “In addition, since themechanisms of neurodegenerativedisorders sometimes show similarities,it would be interesting to investigatewhether p53 is involved in Parkinson’sdisease or in amyotrophic lateralsclerosis.”
Adrian Burton
http://neurology.thelancet.com Vol 4 September 2005 529
For the first time, researchers haveproven that Lorenzo’s oil haspreventive effects in patients withX-linked adrenoleukodystrophy (ALD).“The capacity of this study to reducethe risk of developing the childhoodcerebral form of ALD, at least by a factorof two, and to do so without seriousside-effects is a significant clinicaladvance”, Hugo Moser (KennedyKrieger Institute, Baltimore, MA, USA)told The Lancet Neurology.
ALD is a rare genetic disorder causedby a mutation in the ABCD1 gene,which is located on the X chromosomeand encodes a peroxisomal membraneprotein. The disease is characterised byhigh concentrations of very-long-chainfatty acids (VLCFAs) in the CNS andadrenal cortex, and it affects aboutone in every 25 000 boys. Lorenzo’soil—which contains oleic and erucicacid—was developed in 1984 byAugosto and Michaela Odone aftertheir son, Lorenzo, started to showsymptoms of ALD.
Previous studies with Lorenzo’s oilhave not shown clinical improvementin patients with ALD. However, Moserand colleagues’ recent study is thefirst follow-up study to be done inasymptomatic patients with ALD(Arch Neurol 2005; 62: 1073–80). Theresearchers investigated whether
there was an association betweenlowering the amount of VLCFAs in theplasma with Lorenzo’s oil and diseaseprogression. 89 patients wereidentified by screening at-riskrelatives of patients known to haveALD and patients with Addison’sdisease. A diagnosis of ALD wasconfirmed by use of plasma-VLCFAassay. Before treatment withLorenzo’s oil, all patients had normalMRI and neurological results. Dailyoral doses of Lorenzo’s oil were given,and other dietary fat intake waslimited.
At follow-up 13 years later, Moserand colleagues found an associationbetween the change in plasma-VLCFAconcentrations and the developmentof abnormal MRI or neurological signs.66 patients (74%) had normalneurological and MRI results, 21 (24%)had abnormalities on MRI, and onlyten (11%) had clinical signs ofneurological abnormalities. “Werecommend giving Lorenzo’s oil toasymptomatic boys with ALD, whohave normal MRI and who are youngerthan 8 years”, Moser comments.Moser hopes that this study will leadto the development of technology forneonatal screening, therefore enablingidentification of many more at-riskboys at a very early stage.
In an accompanying editorial,Raymond Ferri and Phillip Chance(University of Washington, Seattle,WA, USA) write that Moser’s researchwas a “remarkable” study and “mayestablish new standards for thetreatment of this degenerativedisorder” (Arch Neurol 2005; 62:1045–46).
Nayanah Siva
Positive effects with Lorenzo’s oil
ALD is a genetic disorder typically affecting young boys
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