Anti-nausea drug helps cells with the hd mutation stay healthy in a surprising way - hdbuzz - huntington’s disease research news.
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Anti-nausea drug helps cells with the HD mutation
stay healthy in a surprising way
Anti-nausea drug meclizine protects cells with the HD mutation from death byreducing cellular energy productionBy on February 04, 2011
The connection between cellular energy levels and HD is more complicated than wepreviously thought, but in a way that opens a door to more possible treatments. It seemsdrugs that actually slow down the production of energy can rescue cells with the HDmutation from dysfunction and death.
Energy in HD
Energy is a big problem in HD. One of the most common symptoms in people with HD is
weight loss: the emaciated facial features of HD patients are immediately recognizable
to many HD family members. Surprisingly, not much is known about how and why this
happens. HD patients generally eat as much as people without HD, if not more, but they
have a hard time keeping on weight. So it seems that the problem is not getting enough
calories, but some problem with using the energy they consume.
Scientists are beginning to understand that one of thejobs of the huntingtin protein is to regulate energyproduction within cells. Dr Marcy MacDonald’s group ofresearchers have shown that in blood cells from HDpatients, longer CAG repeats in the huntingtin gene goalong with lower total energy levels. That’s important,because longer CAG repeat counts tend to produce anearlier age of onset of the disease.
Because of that link between CAG repeats and energy,
researchers have been looking at whether bolstering
energy levels might be helpful in HD. Several trialsunderway, including those with creatine and coenzyme Q10, are based on the idea thatincreasing energy levels in HD will be helpful.
But symptoms in HD are complex - it can be difficult to figure out which symptoms arecausing the disease, and which symptoms are the body’s attempts to deal with it. It’s abit like having a fever - it’s not comfortable, but it’s one way the body fights infections.
So, are reduced energy levels in HD causing the disease, or something the body is doingto cope with another problem we don’t understand?
Could reducing metabolism be good for cells with
the HD mutation?
A surprise came about two years ago, when a team of researchers working with Dr Brent
Stockwell at Columbia university were looking for drugs that rescue cells with the HD
mutation from dying. They found that drugs that slow down metabolism, or energy
production, made cells with the HD mutation healthier.
That caused some confusion - energy levels are low in cells with the HD mutation, andmany HD patients take drugs aimed at increasing their energy levels. Despite this,Stockwell’s team suggested that or slowing down metabolism can protect cells with theHD mutation. Could this be true?
Vamsi Mootha, working with Vishal Gohil and others, has been working to understandthe situation. Energy levels are also important in conditions like heart attack and stroke,where important cells are not getting enough oxygen. Previously, Mootha has shownthat a compound called meclizine protects heart cells from damage caused by lack ofoxygen.
Meclizine works, in part, a bit like the way Stockwell’s
compounds worked, so he tested it in another HD cell
model. Meclizine does turn out to protect cells with the
HD mutation from dying, and it does so by slowing down “
Meclizine does turn
their metabolism, in agreement with Stockwell’s data.
It’s not clear if the effects observed by Stockwell and
Mootha will translate from cells to HD patients. In order
to improve on simple cell models, Mootha examined the
effects of Meclizine in worm and fly models of HD. These
animal models showed some improvements when treated
with Meclizine, but additional studies in mice or rats would be beneficial. Rodent ”
take more resources and time to conduct, which is why scientists often study shorter-lived organisms like flies and worms first.
This set of unexpected findings demonstrates why we have to be very careful with drug
development in HD. On the surface, it’s easy to look at a problem like low energy levels
and conclude that increasing energy levels would help. But, if we dig below the surface,
the picture becomes more complex. It’s still not clear what aspect of metabolism is
damaging cells with the HD mutation, or how it’s helped by Meclizine, but you can be
sure that these scientists are trying to figure it out.
An interesting twist to the story is that Meclizine is already an approved drug - but notfor HD. It’s an anti-nausea drug that’s available over the counter in many countries. It’stoo early for anyone to take any drug based on this research, but it’s heartening to seethat researchers are trying to use drugs in their scientific studies that could quickly
translate to use in humans, once we understand them better.
Jeff Carroll works as a post-doctoral fellow in the lab of Marcy MacDonald, mentioned inthis story. His project involves understanding metabolic alterations in HD. At the time ofwriting, he does not work with Meclizine or any of the other researchers mentioneddirectly.
The protein produced by the HD gene.CAG repeat
The stretch of DNA at the beginning of the HD gene, which contains the
sequence CAG repeated many times, and is abnormally long in people who will
The process of cells taking in nutrients and turning them into energy
and building blocks to build and repair cells.
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