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Indian research on Huntington’s disease

Indian research may have garnered a greater insight into the mechanisms by which Huntington’s disease causes neurological degeneration — providing an avenue by which treatment methods may be developed.

Huntington's disease Image ID: 74913356 (L)Huntington’s disease – also known as Huntington’s chorea – is an incurable, progressive degenerative brain disorder caused by a repeating section of the genetic code for the protein huntingtin (htt). The disease affects between three and seven people per every 100,000 in India and is passed on from parent to child.

The genetic aspect of the disease is well-documented. The htt gene mutation occurs in a DNA segment known as a CAG trinucleotide repeat. This region is repeated and varies from individual to individual. In healthy individuals, this trinucleotide repeat has around ten to 35 repeat sections. Individuals with 36 or more repeats are considered to have a mutated gene and may develop the symptoms of Huntington’s disease.

The symptoms of the disease are more severe — and can occur earlier — the higher the number of repeat sections. Those with 36 to 39 repeats may never experience symptoms (though can pass the disease to their children) while those with forty or more repeats almost always display symptoms.

The disease is inherited in an autosomal dominant pattern, meaning that only one parent needs a copy of the mutated gene in order to cause the disorder in their children. The size of the CAG repeat can increase when it is passed on to the children, meaning that the disease can develop even in those with no family history of the condition.

In addition, high repeat counts can cause a condition known as juvenile-onset Huntington’s disease. In these instances the individual can develop the disease before the age of 21 as opposed to the standard age of onset which occurs between in an individual’s thirties or forties.

Early signs and symptoms can include irritability, depression, small involuntary movements, poor coordination, and trouble learning new information or making decisions. As the disease progresses the loss of control over the muscles causes the affected individual to be unable to care for themselves, often becoming housebound. In time, the loss of muscle function can interfere with processes such as swallowing and breathing, eventually becoming fatal through issues such as heart failure and pneumonia.

The symptoms of the disease are caused by the abnormally long mutant huntingtin proteins being cut, and aggregating upon themselves. These aggregates are referred to as “sticky” and can bind many other proteins and cellular structures, causing toxicity within the neurons and eventually cell death within the brain.

The Indian study, led by Dr Amitabha Majumdar at National Centre for Cell Science (NCCS) in Pune, assesses the role the mutant htt plays in translation — the process by which proteins are created from the DNA code.

The study found that translation dysfunction could at least partly explain the mechanism by which mutant htt induces cellular toxicity. It was found that a protein synthesis deficit occurred in cells overexposed to mutant htt. Such protein synthesis dysfunction, and the corresponding lack of available proteins within the cell, could cause any number of cellular defects (depending on which proteins were in short supply). This could explain the process by which neuronal atrophy, and eventual cell death occurs.

It was found that the protein translation regulator Orb2 was sequestered and inhibited in the presence of mutant htt, which may be the mechanism by which the protein synthesis disruption occurs. Importantly, it was found that co-expression of Orb2 can partially rescue the lethality associated with mutant htt — this would implicate the use of human analogues of Orb2 as a potential therapeutic agent in the treatment of Huntington’s disease — warranting further trials.

Treatments for Huntington’s disease focus on symptom management, as the disease is currently neither reversible nor is its progress able to be slowed. The treatments can often involve the administration of a cocktail of antipsychotics, antidepressants and tranquilisers to keep symptoms in check.

Research from the Indian team could well have pointed clinical research in the right direction to addressing the actual causes of Huntington’s disease, rather than to simply attempt to alleviate the symptoms. While in its early stages, this research could be the beginning of the path to providing real change for those with Huntington’s disease, and, while only partially alleviating the toxicity of mutant htt, the use of Orb2 may well be the future method to slow the progress of the disease.

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