Signs of oxidative stress found in HD human brain samples

HD Lighthouse Contributing Editor's Comment: 

For some time now, Lighthouse readers have been following the proactive strategy of eating high antioxidant foods and/or taking supplements.  At the same time, antioxdiants are in clinical trials for the disease.  The idea behind this is that oxidative stress appears to be a major pathology in Huntington's Disease.

Energy for cellular processes is produced in the mitochondria. During the process, free radicals are produced. This is a molecule of oxygen with only one electron, not with two electrons that are bonded together, which is the normal form of oxygen. This means it can go scavenge for other molecules to bond with.  Normally this isn't a problem because nearby antioxidants will bond with the free radicals and render them harmless. When there are too many free radicals and not enough antioxidants, they can do a lot of damage. This process is called oxidative stress; free radicals go scavenging and can destroy cellular compounds and damage proteins, lipids, and DNA, and lead to cell death - especially in the brain which generates more oxidative by products than other organs of the body.

With normal aging, our antioxidant defense system becomes less efficient.  There is also evidence that oxidative stress also occurs in all of the neurodegenerative disorders.  In their analysis of HD brain samples, researchers from the University of Lleida found proteins in the striatum and cortex which are associated with the activation of the brain's antioxidant response.

The study adds to the evidence that oxidative stress is a factor in HD pathology and reinforces the HDL strategy of adding foods to one's diet that are rich in antioxidants.  For a list of foods highest in antioxidants, click here: http://hdlighthouse.org/treatment-care/care/hdltriad/diet/updates/1116antioxidant.php  

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 01-01-2009

Proteomic and oxidative stress analysis in human brain samples of Huntington disease.

M Alba Sorolla, Gemma Reverter-Branchat, Jordi Tamarit, Isidre Ferrer, Joaquim Ros and Elisa Cabiscol

press release:

Therapeutic strategies to strengthen antioxidant defenses could help to prevent the progression of Huntington's Disease. This is the suggestion from the results of the first ever trial on human samples carried out by researchers at the University of Lleida. The results have been published in the latest issue of Free Radical Biology & Medicine magazine.

A study carried out by Catalan researchers shows that oxidative stress and damage to certain macromolecules are involved in the progression of Huntington's Disease (HD), which is characterised by psychiatric and cognitive disturbance, involuntary movements (chorea) and dementia.

The research was carried out using human brain samples obtained post mortem from people affected by HD, which were compared with samples from control patients (C) who had died from unrelated illnesses or other causes. The two cerebral areas most affected by this illness the striate cortex and cortex were studied.

The samples, which were provided by the tissue bank at the University of Barcelona's Institute of Neuropathology, were divided into HD-C group pairs based on gender, age, and the length of time after death before the tissue had been removed.

"Bidimensional electrophoresis techniques were used to compare the differences between the proteins present in the brains of the sick people and those of the controls," said Elisa Cabiscol, professor of biochemistry at the University of Lleida, and one of the report's authors. "The results showed that more than half of these were enzymes related to antioxidant defence systems."

This study, which used human samples for the first time and was funded by Spain's Consolider-Ingenio 2010 Programme, found that the brain tissue from people suffering from HD had elevated levels of proteins that eliminate reactive oxygen species (ROS), or free radicals, as they are more commonly known.

"There is a situation we call oxidative stress in the brains of these patients, and as a result the neurones (and other cells in the brain, such as the glia cells) attempt to defend themselves by increasing their antioxidant defences," said Cabiscol.

In normal conditions, the balance between ROS generation and antioxidant systems allows cells to function correctly. However, in a situation of oxidative stress, ROS generation exceeds the cells' defence capacity, causing changes in the cells that ultimately cause them to die.

"Our proteomic study has made clear how important a role oxidative stress plays in this illness, calling for the use of therapeutic strategies that boost antioxidant defences or prevent the formation of ROS, on order to try to halt or slow down the progression of this devastating disease," added the researcher.

Huntington's Disease

HD is caused by degeneration of cells in the brain, the neurones, as a result of genetic changes. The symptoms of this disease that runs in families first become apparent in middle age, and it progresses over 15 to 20 years before leading to an inevitable death. Both the speed at which the disease progresses and the age of onset varies from one person to another.

Mutation on the /htt/ gene generates an abnormal protein (huntingtin), which has a 'polyglutamine tail'. These polyglutamines eventually cause the protein to form aggregates. "What we still don't understand is the function of this protein, and how the presence of these aggregates causes the neurones in certain areas of the brain to malfunction and die," said Cabiscol.

Statistical estimates show that one in every 10,000 people suffers from HD, translating into more than 4,000 sufferers in a country such as Spain. However, Montse Torrecilla, secretary of the Spanish Huntington's Chorea Association (ACHE), says there is a lack of real data on the number of patients. "This is a complex issue, because one has to bear in mind the number of misdiagnoses and people who hide, or are still not aware of, their illness," she said.

abstract

Huntington disease (HD) is a neurodegenerative disorder caused by expansion of CAG repeats in exon 1 of the huntingtin gene, affecting initially the striatum and progressively the cortex. This work reports a proteomic analysis of human brain postmortem samples obtained from striatum and cortex of patients with HD compared to samples of age- and sex-matched controls. Antioxidant defense proteins that were strongly induced in striatum, but also detectable in cortex, were identified as peroxiredoxins 1, 2, and 6, as well as glutathione peroxidases 1 and 6. The activities of other antioxidant enzymes such as mitochondrial superoxide dismutase and catalase were also increased in HD. Aconitase, a protein involved in energy metabolism, showed decreased activities in striatum of HD patients. Protein carbonyls, used as markers of oxidative stress, were increased in HD, and glial fibrillary acidic protein, aconitase, gamma-enolase, and creatine kinase B were identified as the main targets. Taken together, these results indicate that oxidative stress and damage to specific macromolecules would participate in the disease progression. Also, these data support the rationale for therapeutic strategies that either potentiate antioxidant defenses or avoid oxidative stress generation to delay disease progression.

Source: Free Radical Biology & Medicine 2008 Sep 1;45(5):667-78. Epub 2008 May 28