Conclusions and Proposals for Future Work

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.

Figure 1: Depiction of mutant Huntingtin forming aggregates that can disrupt cell function, interact and strap fragments of other protein and other useful molecules.

Prevent Aggregation

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.

Figure 2: Degradation of mHtt fragments and aggregates. Proposal is to attach protein that can rapidly signal for degradation by proteosome and autophagy. Edited Image. Orginal Image from:


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)

4 Replies to “Conclusions and Proposals for Future Work”

  1. Both proposals you mention involve designing a protein that would be used to treat Huntington’s disease, have you come across any other treatment techniques for Huntington’s such as RNAi? How would the protein (and the RNAi) treatment be delivered? Is there currently any research into drugs that could interact with mHtt protein? If a protein or drug is designed to interact with the poly-Q region in mHtt, would there need to be numerous variants of these proteins/drugs developed to interact with the specific number of glutamine repetitions present in each patient’s mHtt?

    1. I was able find some research that investigated the efficacy of treating Huntington’s disease with RNAi. This method relies on targeting SNPs in a patients Htt gene and can be delivered by adeno-associated virus 2 (AAV2) and AAV5 mediated viral vector delivery of short hairpin RNA. More research must be put into using RNAi, as it could potentially do more harm than good. (Lombardi et al. 2009) There have been a couple of protein delivery methods for degenerative diseases. Proteins to treat Huntington’s can be delivered using encapsulated cells. (Aebischer 2001) If a protein or drug was designed to interact with the Poly-Q region, it may be designed so that it takes advantage of the polyQ expansion, recognizing more than 36 glutamines by hydrogen bonding with the poly Q region. Though designing proteins to recognize a certain number of glutamines could tighten the protein-huntingtin interaction.

      Aebischer, Patrick, and Jean-Luc Ridet. “Recombinant proteins for neurodegenerative diseases: the delivery issue.” Trends in neurosciences 24, no. 9 (2001): 533-540.

      Lombardi, Maria Stella, Leonie Jaspers, Christine Spronkmans, Cinzia Gellera, Franco Taroni, Emilio Di Maria, Stefano Di Donato, and William F. Kaemmerer. “A majority of Huntington’s disease patients may be treatable by individualized allele-specific RNA interference.” Experimental neurology 217, no. 2 (2009): 312-319.

  2. I would like to first commend you for taking on such a difficult topic. Huntington’s disease is a very interesting condition because it displays very unique quirks of biochemistry and genetics (some of which you touched upon such as autosomal dominant, trinucleotide repeats, and protein aggregation). However, these idiosyncrasies can make the disease difficult to fully appreciate. There are some other characteristics of Huntington’s that, if explored more, can highlight some of the stranger aspects of the disease. For one, the disease demonstrates anticipation or where the symptoms progressively worsen and have earlier onset with each generation. Furthermore, HD’s anticipation is paternal in that there is preferential expansion of the CAG repeats during spermatogenesis; basically this means that the earlier onset is typically only seen when it is inherited from the father. In fact, if inherited from the mother, there is evidence that the repeats are actually imprinted and therefore the disease is less severe. Another interesting aspect of HD is the interplay between the loss of GABAergic inhibition of dopamine and the destruction of the medium spiny striatal neurons of the caudate nucleus. This increased activity of dopamine is the basis for the disease-defining chorea (fun fact: “chorea” is derived from the Greek word for dance). As you highlighted, there is a lot that remains to be discovered when it comes to the pathophysiology of Huntington’s. I thank you for your work on such a fascinating, yet challenging, topic.

    1. Thank you, those are extremely interesting aspects of Huntington’s. I’m surprised that none of the articles and reviews I looked into mentioned that HD’s anticipation is paternal, or maternal inheritance is subject to imprinting.

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