Potential for New Huntington’s Disease Diagnostics

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Potential for New Huntington’s Disease Diagnostics

working on medical research in science laboratory/ Photo By SeventyFour via Shutterstock


A pair of recent studies examining the protein responsible for Huntington’s disease have opened up new potential for diagnostic development by finding a new mutation associated with the disease and reliably identifying the protein in saliva.


Huntington’s disease is inherited


Huntington’s disease or chorea is an inherited autosomal dominant progressive neurodegenerative disorder. It is characterised by a general lack of coordination and unsteady gait. Mood disorders and decline into dementia may occur. Coordination continues to worsen until the person cannot walk. It may occur at any age and about 8% of cases occur before the age of 20.

Autosomal dominant means the disease can be caused by a single faulty copy of the HTT gene, even in the presence of a normal copy. The causal mutation is an abnormally lengthy trinucleotide repeat present within the gene. This is known as the polyQ region of the protein, Q being the single letter code for the amino acid glutamine.

A trinucleotide repeat count of less than 26 is considered completely normal and will result in no disease. Repeats of 27-35 are in the danger zone, the carrier will most likely be unaffected, however, their children have a low chance of suffering from the disease. Repeats of 36-39 may be affected and their children have a 50% chance of having the disease. Above 40 repeats will result in the disease and again the children will have a 50% risk of the disease. Due to repeat expansion, Huntington’s tends to occur at earlier and earlier ages within families.

The normal Huntington protein (HTT) is expressed in all the cells in the body and interacts with over 100 other proteins. The mutant HTT is toxic to certain cells of the brain. The mutant HTT is easily cut by other enzymes in the body which leads to it forming fibrillar aggregates. Ultimately the aggregates form inclusion bodies that interfere with neuron function. There is currently no treatment to delay the onset of symptoms.


A new mutation in Huntington protein has been identified


A new study by M. R. Hayden from Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada, and colleagues have identified a new modification of the Huntington protein which occurs exclusively in East Asian people.

The modification prevents Myristoylation of the protein which involves the addition of the 14 carbon fatty acid myristate. The myristate normally promotes the membrane binding of proteins. This single nucleotide polymorphism (SNP) promotes the toxic cutting of the HTT protein resulting toxicity towards cells.

This study has revealed a new potential risk factor for Huntington’s disease and is also the first time a modification to myristoylation has been demonstrated. With further validation, this SNP can now be incorporated into Huntington disease diagnostics. The work was published in the journal Scientific Reports.


Potential found for developing a protein-based saliva diagnostic


Further work on the potential diagnostic front has been achieved by Elizabeth A. Thomas of the Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA and colleagues which were also published in the journal Scientific Reports. Although HTT could be detected by a DNA test, protein is the definitive test as this is the disease-causing agent.


research team in a laboratory/ Photo By ProStockStudio via Shutterstock


Elizabeth Thomas and colleagues sought to develop a non-invasive saliva-based test for HTT protein. Many therapies that aim to treat Huntington disease aim to do so by lowering the protein levels of mutant HTT that form the toxic aggregates. Therefore, a saliva test would be useful for monitoring the course of a treatment with experimental drugs aimed at lowering the levels of HTT.

The team was able to detect HTT protein in the concentrated saliva of healthy and diseased individuals using a protein detection technique known as Western blotting that separates proteins based on their size by migrating them through a gel with a complex porous route. The HTT protein level was also detectable by a different method known as ELISA.

The team also found that they could reliably detect mutant HTT in Huntington disease patients but not healthy people. Importantly the levels of mutant HTT in the Huntington patients significantly correlated with clinical measures of the disease such as the Huntington’s Disease Rating Scale (UHDRS). Further studies are needed to determine if salivary levels of HTT correlate with levels of HTT found in the blood

The study also highlights the growing trend of using saliva as a diagnostic specimen to detect a biomarker of protein. Proteomic studies have found more than 2,000 proteins in saliva, of which 27% are also present in blood. Given that saliva can be collected non-invasively it is the ideal location to begin diagnostic development.

Furthermore, with the use of DNA sequencing, the complete patient genome can be generated. Given the depth of knowledge about Huntington disease genetics, it should be possible to predict Huntington’s Disease directly from a person’s genome sequence.

This recent pair of reports opens up new opportunities for diagnostic development for Huntington’s disease which are very much in demand as there are currently no treatments available. The ability to accurately monitor the course of the disease could greatly aid in the development of new treatments particularly at the clinical trial stage where every extra piece of evidence is crucial to extracting the maximum value from a trial to treat the disease.




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