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http://neurology.thelancet.com Vol 4 February 2005 83

According to the results of a preclinicalstudy, the antineoplastic agentpaclitaxel may have the potential totreat neurodegenerative disorderssuch as Alzheimer's disease (AD).When a low or medium dose of themicrotubule-binding drug was givento transgenic mice, it improved axonaltransport, increased microtubules, andimproved motor impairment (ProcNatl Acad Sci USA 2005; 102:227–31).

The neurofibrillary tangle, whichcontains paired helical filaments thatseem to be mainly formed fromabnormal aggregations of tauproteins, is a pathological hallmark ofAD. Normal tau stabilises andmaintains microtubule networks thatare essential for axonal transport in

neurons, and tau dysfunction has beenimplicated in mechanisms underlyingmany neurodegenerative diseases.

As an analogy, study author John Trojanowski (University ofPennsylvania School of Medicine,Philadelphia, PA, USA) says to “thinkof tau as the cross-tie of themicrotubule train track. If you pull offthe cross-ties, the trains wobble andfall off the tracks”.

Although most research is focusedon therapeutics to break apart theaggregated proteins and plaques thatcharacterise AD, for the past decadeTrojanowski and colleagues have beenexploring the more novel concept ofdrugs to stabilise microtubules. Inmice, symptoms manifest as a motordefect rather than the memory defect

that occurs in human beings, explainsTrojanowski, but the type ofpathology is the same.

The researchers did a preclinicalproof-of-concept trial in which trans-genic mice received intraperitonealinjections of either 10 mg/m2 or25 mg/m2 of paclitaxel for a period of12 weeks. Whereas the tangles werenot eliminated, microtubules in micetreated with both low and high doseswere increased (32% and 49%), andthe fast axonal transport deficit wascorrected by stabilisation of themicrotubules. Motor impairment wasalso ameliorated in the treated mice.

“This does prove our hypothesisthat microtubule stabilising drugscan make up for the loss of tau thatresults when the tau is bundled

Microtubule-stabilising drugs may be therapeutic in AD

Researchers have identified a targetgene of MECP2, a protein that iscommonly mutated in the childhoodneurodevelopmental disorder Rett’ssyndrome. Terumi Kohwi-Shigematsu(Lawrence Berkeley NationalLaboratory, Berkeley, CA, USA) and hercolleagues report that loss of Mecp2activity in mice causes overexpressionof Dlx5, a transcription factorimportant for GABAergic neuronactivity.

Rett’s syndrome affects one in10 000–15 000 female births. Affectedindividuals develop normally until6–18 months of age, after which theyrapidly regress, losing speech and motorskills and developing stereotypic handmovements, ataxia, seizures, andautism.

MECP2 was identified as the genemutated in Rett’s syndrome in 1999.The protein encoded by MECP2 bindsto methylated CpG dinucleotides inDNA and is a transcriptional repressor.“MEC2P mutations may cause thefaulty overexpression of MEC2P targetgenes, particularly in the brain, so we

set out to identify these genes”,explains Kohwi-Shigematsu.

Her team sequenced 100 regions ofgenomic DNA that bound Mec2p inmouse brains. Several of these mappedto an imprinted gene cluster (an areaenriched in genes that are transcribedonly from the maternal or paternalallele) containing Dlx5. In the brains ofMec2p-null mice, explains Kohwi-Shigematsu, Dlx5 was transcribed twiceas much as in normal mouse brain.DLX5 expression was also slightlyincreased in lymphoblastoid cells frompeople with Rett’s syndrome andoccurred from both alleles of the gene,suggesting that DLX5 expression wasincreased through loss of imprinting.Finally, unexpectedly, the absence ofMecp2 in the mice caused changes inthe higher order folding of thechromatin at the Dlx5 locus (Nat Genet2005; 37: 31–40).

“The finding that loss of Mecp2increases Dlx5 expression is veryinteresting”, comments SchahramAkbarian (University of MassachusettsMedical School, Worcester, MA, USA),

“but it remains to be seen whether thisalteration results in the dysfunction ofGABA neurons in the Mec2p-deficientbrain”. This is work that Kohwi-Shigematsu has underway and, sheadds, “if our results confirm that MEC2Pmutations do cause GABA dysregula-tion, it may be possible to find ways toregulate GABAergic neuron activity inindividuals with Rett’s syndrome andthus reduce some of their symptoms”.

Jane Bradbury

Advance made in understanding Rett’s syndrome

Rett’s syndrome affects mostly females

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or sequestered in tangles”, saysTrojanowski.

“It has in the past been widelyassumed that the dementia of ADresults from loss of synapses or, evenworse, loss of neurons”, commentsSimon Lovestone (Institute ofPsychiatry, King’s College London,UK), who has performed related

research with drosophilia. “Replacingsynapses is difficult and replacingneurons even tougher.”

However, evidence is building whichsuggests that there may be neuronaldysfunction resulting from taudysregulation, he adds. “For patientsthis suggests that it is at leastconceivable that the early clinical

manifestations of pathology could bereversed and not just halted ordelayed. This raises the stakes forpossible disease modification therapyin AD although, of course, studies inflies and mice are a very long way fromhuman benefits.”

Roxanne Nelson

84 http://neurology.thelancet.com Vol 4 February 2005

Two recent studies have added weightto the theory that a calorie-restricted(CR) diet may protect againstneurodegenerative disease and givesome clues to the underlyingmechanisms.

In the first study, Mark Mattson(National Institute on Aging,Baltimore, MD, USA) and colleaguesinvestigated the effect of a CR diet onneurochemical deficits and motordysfunction in an animal model ofParkinson’s disease (PD). Theresearchers induced hemiparkinsonismin two groups of rhesus monkeys byinjection of the dopaminergicneurotoxin MPTP in to the rightcarotid artery. One group had beengiven a CR diet (a 30% reduction incalorie intake) for 6 months beforeMPTP injection and a control grouphad been given a normal diet (Proc NatlAcad Sci USA 2004; 101: 18171–76).

Within 24 h of MPTP lesion, Mattsonand colleagues saw parkinsonian

symptoms—limb rigidity, reducedmotor activity, and action tremor—inboth groups. However, when theymeasured the motor deficit 6–8 weeksafter lesioning, the researchers foundthat the reduction in distance movedand movement speed was significantlyless in the CR diet group than in thecontrol group. These findings weresupported by the results ofneurochemical analyses: concentra-tions of dopamine and two of itsmetabolites in the right striatum werehigher in the CR diet group than in thecontrol group. In addition, theresearchers found that concentrationsof glial-cell-line-derived neurotrophicfactor (GDNF), were significantly higherin the right caudate nucleus in the CRdiet group than in controls. The authorsconclude that this upregulation ofGDNF production may underlie theprotective effects of a CR diet.

“Our findings suggest a preventivestrategy, but their implications forthose who are already affected areunclear”, comments Mattson. “Indeed,there is no evidence that diet canaffect the disease process in patientswith PD”. In an accompanyingcommentary on the article (Proc NatlAcad Sci USA 2004; 101: 17887–88),Caleb Finch (University of SouthernCalifornia, Los Angeles, LA, USA)writes that “it seems timely tocompare the incidence ofparkinsonism in those who strive toreduce . . . excessive body fat by meansof CR or yo-yo diets and in those whohave long maintained a low fat intakeand body mass index”.

In a second study, Finch’s group atthe University of Southern Californiainvestigated the effect of a CR diet in two transgenic mouse modelsof Alzheimer’s disease expressingmutant amyloid precursor protein andmutant presenilin 1. “In bothtransgenic lines CR reduced amyloidbeta (A�) immunoreactivity by nearly50%”, explains Todd Morgan, one ofthe authors. Morgan and co-workersalso found a decrease in immuno-staining for glial fibrillary acidic protein(Neurobiol Aging 2004; publishedonline Nov 25, DOI: 10.1016/j.neurobiolaging.2004.09.014). “Thesimultaneous reduction of both glialactivity and A� deposition areconsistent with prior suggestions forthe direct role of activated astryocytesin plaque genesis”, concludes Morgan.

However, the effect of diet onneurodegenerative disease in humanbeings is a contentious issue: somestudies suggest that certain dietaryfactors may be protective, but theevidence is inconclusive (Lancet Neurol2004; 3: 579–87), and many factorsare thought to be involved. “Theoverall evidence from this study andother areas in the field of dementiaappears to support a healthy balanceof calorie intake and output”,comments Martha Clare Morris (RushInstitute for Healthy Aging, Chicago,IL, USA). “This may be betterinterpreted as maintaining a healthyweight rather than severely restrictingcalories”.

Rebecca Love

Calorie restriction may be neuroprotective in AD and PD

Could calorie restriction be neuroprotective?

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