Huntingtin and Huntington's Disease


This page was created as a project for Genetics 677 at UW-Madison in the spring of 2009


Discussion


Overview

          The focus of this project is to obtain data about the HTT gene and huntingtin utilizing the full extent of bioinformatics tools available in order to characterize the genetic basis of Huntington’s disease.  Throughout the semester, I took a variety of approaches to assess the pathological role of huntingtin, the results of which I feel present a relatively detailed description of Huntington’s disease at the genetic level.  Reviewing a popular press article written about the discovery of the HTT gene indicated the widespread research dedicated to Huntington’s disease, and the relative difficulty with which the gene emerged as the basis of the disorder.  Since this initial discovery in 1993, researchers managed to characterize both the gene and protein to an extremely detailed extent, yet much information remains awaiting discovery.  An initial analysis of the extent to which huntingtin is shared in other species, through a comparison of the human sequence to homologous genes in other species, indicated the protein is extremely well conserved within vertebrate species, including samples of mammals, birds, and fish.  Yet, while the protein appears largely identical in a large number of species, only humans and chimpanzees appear to contain the CAG trinucleotide repeat region responsible for the disease.  Characterizing the protein domains in the human sequence demonstrated a generally sparse amount of information regarding functional regions of the protein, yet the one well characterized region within the protein, the HEAT repeat domains, reveals the basic function of huntingtin.  HEAT repeat domains mediate protein-protein interactions, which at a basic level describe the proposed, base function of huntingtin as a facilitator of protein interactions in vesicular transport, which is also confirmed by the gene ontology terms associated with the protein.  Assessing the protein interactions of huntingtin reveals the relatively complex and currently unidentified function of the protein in the cell.  Huntingtin interacts with an extremely large number of proteins in the cells, affecting pathways including vesicle trafficking, transcriptional regulation, calcium ion homeostasis, mitochondrial function, and the induction of apoptosis.  Thus, some of the important pathological implications of the cleaved, aggregated huntingtin protein emerge.  One of the pathways apparently altered by mutant huntingtin is the normal transcription of genes integral to normal neuron function.  Microarray analyses conducted on a Huntington’s disease mouse model demonstrated reduced transcription in a wide spectrum of genes, resulting from a proposed mechanism involving the binding of key transcription factors.  Finally, a review of current drug interaction experiments conducted on huntingtin identified the wide variety of techniques currently in research to treat Huntington’s disease, which includes the clearance of the aggregated protein and the restoration of normal neurotransmitter function in striatal cells. 

Future directions

        The most striking feature of the current state of research on huntingtin is the lack of information regarding the normal function of the protein.  Indeed, researches uncovered the basic function of huntingtin as a mediator of vesicular transport, but a thorough and detailed analysis of the precise natural role of the protein in the cell remains relatively ill-described.  Noting the high conservation of huntingtin within vertebrate species and the results of HTT knockout mouse experiments in which the lack of huntingtin resulted in embryonic lethality, the protein must play an extremely important role in development.  Yet this native function remains undiscovered.   I feel one of the key areas of research in the future for huntingtin is uncovering this native role in neuron development which leads to embryonic lethality.  A great deal of effort is focused, rightly so, on the pathological state induced by the mutant protein.  Figuring out the native role of the protein appears to me an important step in assessing the precise pathogenic mechanism of Huntington’s disease.  One step I would like to research to a greater extent is the interaction network of the full length huntingtin protein.  Many of the protein interactions I found resulted from yeast two-hybrid systems utilizing the cleaved N-terminus of huntingtin.  I feel looking at the extent of protein interactions of the full length protein may elucidate a greater understanding of the protein’s native function.  Furthermore, while numerous mouse model experiments exist, continued research in this area should help to determine the native huntingtin function.  Experiments involving the knockout of huntingtin in mice at different stages of development, which to some extent researchers currently do utilize in experiments, could be significant to further developing the present understanding of huntingtin.  Of course, research on the cleaved, aggregated form of huntingtin also may lead to important discoveries in assessing the pathological process of Huntington’s disease.  In particular, determining the precise molecular structure of the aggregated intranuclear inclusions may indicate the pathological function of the cleaved protein.  Finally, the reason for the specific neurodegradation induced by huntingtin within the striatum remains unclear.  A variety of techniques available may lead to the discovery of why huntingtin remains destructive in striatal cells and not other neurons or unrelated cells in the body in which huntingtin is still expressed, which may include microarray experiments, protein modification analyzed through proteomic techniques, or more protein interaction data.  While the current state of research on huntingtin since 1993 indicates a massive effort toward discovering the basis of Huntington’s disease, noting the large amount of information still unknown on the protein may constitute the most interesting aspect of this research project.   

Created by Eric Nickels enickels@wisc.edu    5/9/2009      Genetics 677 Webpage