Mitochondrial problems may underlie Huntington's disease

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THE LANCET Neurology Vol 1 August 2002 http://neurology.thelancet.com 203

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The genetic mutation responsible forHuntington’s disease (HD) causescalcium handling problems inmitochondria, a recently publishedstudy reveals. The mitochondria arethen unable to maintain a normalcalcium concentration in key neurons.Once concentrations become too high,cell damage or cell death follow.

“The link between Huntington’sand mitochondrial dysfunction haslong been suspected but this is the firststudy to demonstrate the molecularmechanism involved; this is animportant scientific advance”, com-ments Elena Cattaneo (Center ofExcellence on NeurodegenerativeDiseases, University of Milan, Italy).

Alexander Panov and colleagues,directed by Timothy Greenamyre(Emory University School ofMedicine, Altanta, GA, USA),investigated how the mutation in theprotein huntingtin (Htt) affectsmitochondrial calcium homeostasis.

Mitochondria from patients with HD were were found to haveconsistently lower membrane potentials

and to depolarise at lower calcium loadsthan those from healthy controls. Asimilar defect was found inmitochondria from the brains oftransgenic mice expressing full-lengthmutant Htt, and this defect precededthe onset of pathological or behaviouralabnormalities by several months.

The mutation in Htt is a CAGtrinucleotide expansion that causes apathologically long polyglutaminerepeat in the translated protein.Greenamyre’s group used electronmicroscopy studies to show thatmutant Htt was present on neuronalmitochondrial membranes. Further-more, by incubating normalmitochondria with a fusion proteincontaining an abnormally longpolyglutamine repeat, they alsoreproduced the mitochondrial calciumdefect; this finding suggests that themutant protein may affectmitochondrial function directly. [NatNeurosci; published online July 1; DOI:10.1038/nn884]

“Currently, doctors can only treatthe symptoms of Huntington’s disease:

involuntary movements, loss ofintellectual faculties, speech andswallowing problems, and depression.Understanding more about how theHtt mutation affects nerve cells at themolecular level should provide usopportunities to target the causes”,says Greenamyre. Although furtherstudies need to be carried out tocharacterise the mitochondrial abnor-malities and to understand why onlystriatal neurons die in the disease,Greenamyre is hopeful that drugsalready in use to improve mitochon-drial function might prove beneficialfor HD patients. “I agree, and I alsothink that this study suggests newtargets for drug development, such asthe specific structure—termed thepermeability transition pore (PTP)—that is altered by the presence ofmutant Htt. The PTP–polyglutamineassociation leads directly to abnormalmovements of calcium out of themitochondria and is also implicated inother neurological diseases”, addsCattaneo.Kathryn Senior

Mitochondrial problems may underlie Huntington’s disease

Huntington’s disease drives mother to murderA horrifying article in the New YorkTimes, June 21, told of a 63-year-oldwoman who murdered her sons, aged41 and 42, as they lay asleep in theirroom in a nursing home. Both sonshad Huntington’s disease. Theirmother, who had nursed their fatherthrough the disease until his death andthen devoted most of her time tocaring for her sons, “could no longerbear their suffering”, according tofamily members. She is charged withtwo counts of murder, although asurviving son, 38, who is in the earlystages of the disease, said Huntington’shad killed his brother “long before” agun was fired.

Steven Hersch, head of theHuntington’s disease clinic atMassachusetts General Hospital (Boston,MA, USA) who worked with thewoman and her family, told The LancetNeurology that such a tragedy is“extraordinarily rare”. Nevertheless, itrepresents “the tip of the iceberg with

respect to the incredible burdens thatcaregivers are under for Huntington’sand other neurodegenerative diseases”.In Huntington’s, especially, he says,“the burden is not only taking care ofloved ones; it’s also having all thatknowledge about the disease and itscourse. Knowing what’s coming andhow bad it can be adds tremendouslyto the difficulties they already face ofjust trying to take care of someone.”

Neurologists in such situations“must expand their focus from thepatient to taking care of the wholefamily”, urges Hersch. “A wreckedcaregiver can’t take good care of yourpatient. So your job also becomessupporting the caregiver, who mayneed help, medical care, assistance fordepression or other medical problems.Ask the caregiver if they’re taking careof themselves and help them get theirneeds met, by referring them tosupport groups, community centers,and other health professionals.”

Also important is the role of long-term care. In the USA, says Hersch,“most Huntington’s patients spend athird of their lives in nursing homes,where they tend not to be wantedbecause they take more effort thanother patients. They’re younger andstronger, but the disease affects themphysically, emotionally, and mentally,so they have a reputation as ‘problem’patients because their behaviouralproblems—upset about deviations inroutine, difficulty communicating—can be hard to deal with.”

Although the outlook is presentlygrim for patients with advanced diseaseand their families, “there’s a bigpipeline of agents building”, enthusesHersch, “and I think we’ll havesomething that slows downHuntington’s within 10 years. Thecompounds are there and coming. Itjust takes a long time to do the work inhuman trials.”Marilynn Larkin