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For personal use. Only reproduce with permission from The Lancet Publishing Group. THE LANCET Neurology Vol 1 August 2002 http://neurology.thelancet.com 203 Newsdesk The genetic mutation responsible for Huntington’s disease (HD) causes calcium handling problems in mitochondria, a recently published study reveals. The mitochondria are then unable to maintain a normal calcium concentration in key neurons. Once concentrations become too high, cell damage or cell death follow. “The link between Huntington’s and mitochondrial dysfunction has long been suspected but this is the first study to demonstrate the molecular mechanism involved; this is an important scientific advance”, com- ments Elena Cattaneo (Center of Excellence on Neurodegenerative Diseases, University of Milan, Italy). Alexander Panov and colleagues, directed by Timothy Greenamyre (Emory University School of Medicine, Altanta, GA, USA), investigated how the mutation in the protein huntingtin (Htt) affects mitochondrial calcium homeostasis. Mitochondria from patients with HD were were found to have consistently lower membrane potentials and to depolarise at lower calcium loads than those from healthy controls. A similar defect was found in mitochondria from the brains of transgenic mice expressing full-length mutant Htt, and this defect preceded the onset of pathological or behavioural abnormalities by several months. The mutation in Htt is a CAG trinucleotide expansion that causes a pathologically long polyglutamine repeat in the translated protein. Greenamyre’s group used electron microscopy studies to show that mutant Htt was present on neuronal mitochondrial membranes. Further- more, by incubating normal mitochondria with a fusion protein containing an abnormally long polyglutamine repeat, they also reproduced the mitochondrial calcium defect; this finding suggests that the mutant protein may affect mitochondrial function directly. [Nat Neurosci; published online July 1; DOI: 10.1038/nn884] “Currently, doctors can only treat the symptoms of Huntington’s disease: involuntary movements, loss of intellectual faculties, speech and swallowing problems, and depression. Understanding more about how the Htt mutation affects nerve cells at the molecular level should provide us opportunities to target the causes”, says Greenamyre. Although further studies need to be carried out to characterise the mitochondrial abnor- malities and to understand why only striatal neurons die in the disease, Greenamyre is hopeful that drugs already in use to improve mitochon- drial function might prove beneficial for HD patients. “I agree, and I also think that this study suggests new targets for drug development, such as the specific structure—termed the permeability transition pore (PTP)— that is altered by the presence of mutant Htt. The PTP–polyglutamine association leads directly to abnormal movements of calcium out of the mitochondria and is also implicated in other neurological diseases”, adds Cattaneo. Kathryn Senior Mitochondrial problems may underlie Huntington’s disease Huntington’s disease drives mother to murder A horrifying article in the New York Times, June 21, told of a 63-year-old woman who murdered her sons, aged 41 and 42, as they lay asleep in their room in a nursing home. Both sons had Huntington’s disease. Their mother, who had nursed their father through the disease until his death and then devoted most of her time to caring for her sons, “could no longer bear their suffering”, according to family members. She is charged with two counts of murder, although a surviving son, 38, who is in the early stages of the disease, said Huntington’s had killed his brother “long before” a gun was fired. Steven Hersch, head of the Huntington’s disease clinic at Massachusetts General Hospital (Boston, MA, USA) who worked with the woman and her family, told The Lancet Neurology that such a tragedy is “extraordinarily rare”. Nevertheless, it represents “the tip of the iceberg with respect to the incredible burdens that caregivers are under for Huntington’s and other neurodegenerative diseases”. In Huntington’s, especially, he says, “the burden is not only taking care of loved ones; it’s also having all that knowledge about the disease and its course. Knowing what’s coming and how bad it can be adds tremendously to the difficulties they already face of just trying to take care of someone.” Neurologists in such situations “must expand their focus from the patient to taking care of the whole family”, urges Hersch. “A wrecked caregiver can’t take good care of your patient. So your job also becomes supporting the caregiver, who may need help, medical care, assistance for depression or other medical problems. Ask the caregiver if they’re taking care of themselves and help them get their needs met, by referring them to support 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 a third of their lives in nursing homes, where they tend not to be wanted because they take more effort than other patients. They’re younger and stronger, but the disease affects them physically, emotionally, and mentally, so they have a reputation as ‘problem’ patients because their behavioural problems—upset about deviations in routine, difficulty communicating— can be hard to deal with.” Although the outlook is presently grim for patients with advanced disease and their families, “there’s a big pipeline of agents building”, enthuses Hersch, “and I think we’ll have something that slows down Huntington’s within 10 years. The compounds are there and coming. It just takes a long time to do the work in human trials.” Marilynn Larkin

Mitochondrial problems may underlie Huntington's disease

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For personal use. Only reproduce with permission from The Lancet Publishing Group.

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

Newsdesk

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