Treatment of Symptoms
Treatment of Huntington’s Disease occurs mainly after the onset of symptoms and is primarily administered to attempt control the symptoms. Though symptom control does not offer as much promise as treatments for the cellular dysfunction and damage of Huntingtin’s Disease, it is still necessary to continue research into methods that can alleviate the declining condition of those that suffer from Huntington’s. The onset of Huntington’s disease is signifying the beginning of a painful road of diminishing mental and physical ability that eventually leads to death, which attributes to the rate of suicide among people at the onset of HD. However, rather than solely development of treatments and drugs effective after disease onset, it would be more effective to research methods for delaying the onset of disease. Methods that hold off cellular deterioration by reducing oxidative stress or improving the cells ability to degrade mHtt aggregates.
Huntington’s Disease has proven to be an extremely difficult disease to treat. The PolyQ regions of the fragmented mutant huntingtin aggregate and become toxic by entering the nucleus and interfering with normal protein function. The aggregates continue to build up and eventually overcome the cells ability to degrade them via proteasomes or autophagic vacuolisation. An idea for the treating Huntington’s Disease would be to prevent this aggregation or at least slow it so that the cell could continue to remove it as fast as they are formed. This could potentially be done by taking advantage of mutant huntingtin’s PolyQ aggregate formation. Since aggregates mainly form with fragment with more than 36 glutamines, a protein can be designed that also possesses a large polyQ region that can attach to the toxic aggregates. If this protein is rapidly ubiquinated, signaling for degradation by the proteasome, then perhaps aggregate formation will not overcome aggregate degradation. This proposal does pose problems, as PolyQ regions are structural components of other proteins and therefore could also become targets for rapid degradation. A second proposed method would be designing a protein that would block proteolysis of mutant huntingtin, preventing the fragmentation that leads to aggregation. Development of a protein to accomplish this would be quite difficult and can possibly alter the configuration of the mutant huntingtin, reducing its functionality and exacerbating the epigenetic dysregulation. In order other ways of remedying the toxicity caused by mutant huntingtin aggregates it is vital that further research is put in to understand the mechanism by which aggregation causes damage to the cell and prevents normal function.
Understanding and Controlling Epigenetic Dysregulation
Epigenetic dysfunction is another major contributor to the disease state of Huntington’s Disease. Great strides have been made in understanding huntingtin’s normal function in the regulation of transcription and the changes in regulation in the presence of mutant huntingtin. However, the transcriptional regulators such as HDAC and specificity protein 1 have a large array of targets, thus mutant huntingtin cause broad changes in gene expression in numerous genes and the changes can vary in different tissue throughout the body. Therefore, finding evidence of changes to gene expression that contribute to the disease state of Huntington’s Disease along with a treatment method to fix the dysregulation can be a slow process. The best method to ameliorating the effects of mutant huntingtin on the epigenetics of the cells would be continued research into understanding the effects of mutant huntingtin, and the development of drugs and treatment that can target both large scale dysregulation such as HDAC inhibitors, and dysregulation at enzymes, such as Cysteine y-lyase. (Valor 2015; Paul et al. 2014)