Two Interesting Papers
The first paper is Soluble Androgen Receptor Oligomers Underlie Pathology in a Mouse Model of Spinobulbar Muscular Atrophy.by Li, Chevalier-Larsen, Merry and Diamond.
As is typical of scientific papers, most of us probably have little to no understanding of what this means – although it does sound as if it is an important finding dealing with the reason cells die in SBMA.
The purpose of the study was to try to further understand the molecular processes that cause the nerve cells to die. At this point in time, there are several possible explanations, however, it is not clear which one is correct.
To help in understanding the significance of this paper, it will probably be helpful to review a bit about what is known about SBMA, aka KD. This disease is caused by a mutation in the gene that tells the cells how to make the protein known as the androgen receptor (AR). The AR is the only known protein that mediates the actions of testosterone and its close cousin, dihydrotestosterone (DHT) – these are both in the class of homones knows as androgens and represent those hormones that are sometimes referred to as male homones. In order for testosterone to have an effect on a person’s body, there must be a working androgen receptor. There are, for example, men who have a mutation in their gene for the androgen receptor that may result in a completely inactive form of the androgen receptor. As a result, in the more severe instances, the cells of these individuals cannot respond at all to testosterone in their body. This is known as androgen insensitivity. Importantly, however, these individuals do not have muscular atrophy and do not have any KD symptoms. Thus, it appears that androgen insensitivity is not the cause of KD – since the AR of those with KD is active and appears to work normally, well, at least in most of the cases. As the individual ages and the KD progresses, there are signs of androgen insensitivity, but this is most likely due to the loss in the number of AR molecules in cells as one ages and not due to individual AR not working properly. (You can find more information on androgen insensitivity syndrome at http://www.geneclinics.org/profiles/androgen/details.html.) The cause of KD appears therefore not to be the result of the AR not working but that the mutation results in the production of an AR somehow kills certain cells, scientists say that the AR mutation that causes KD is due to an AR that has gained a toxic property in cells.
One of the most popular suggestions explaining why the cells with the KD mutation are dying is that the cell has trouble eliminating ‘used’ AR. Apparently, once the cell uses the AR (and this is a bit of an exaggeration), the cell then begins the process of destroying the AR protein and recycling its components (amino acids). While it is not completely clear how this is done, it does appear that the cell cannot completely degrade the mutant AR, the type that is make in individuals with high CAG counts in their AR gene. The CAG code in DNA tells the cell to insert a specific amino acid into a protein, the amino acid glutamine (called Q by scientists for some unknown reason!). Thus the high CAG count causes the insertion of a lot of glutamines into the AR when it is being synthesized – this is referred to as the expanded poly Q region. This expanded poly Q region in the AR of KD patients is believed responsible to the inadequate degradation of the AR. A large fragment of the AR remains and this fragment becomes “sticky”. This stickiness is also believed to be due to the expanded poly Q region. As these sticky fragments accumulate, several other cellular molecules become attached to the AR fragment. These fragments are initially still soluble in the cell (they are called oligomers at this stage) but it is thought that this aggregation of cellular molecules eventually leads to the formation of large, insoluble particles (known scientifically as inclusions) in the cells of individuals with KD. In some unknown manner, either the initial soluble fragments or the insoluble inclusions lead to nerve cell death that ultimately causes the loss of muscle tissue characteristic of KD.
This first paper describes the results of research that was attempting to determine whether the soluble fragments or the inclusions were the toxic culprit in KD. These researchers were able to demonstrate that the soluble oligomers actually form in animals models of KD and that properties of these soluble oligomers as such that they appear to be toxic to the cells. These data are consistent with research in other neurological diseases such as Alzheimer’s Disease.
Why we care:
Very simply, this research adds to the understanding of the disease mechanisms of KD. In order to prevent the disease, it is important to understand the mechanisms that cause it. It may be possible, for example, to develop therapeutic agents that prevent the formation of the oligomers and thus prevent cell death.
A second paper recently published on KD, well actually, it is about Huntington’s Disease, is “Ubiquitin-Interacting Motifs Inhibit Aggregation of Poly Q-Expanded Huntingtin” by Miller, Scappini and O’Bryan.
Although KD is an extremely rare disease, we are “fortunate” that KD has many similarities to other similar neurological disease such as Huntington’s Disease (HD) that are more popular to researchers and to funding institutes. Both KD and HD are caused by the expansion of CAG’s in the affected gene – however, the mutations affect different genes and therefore different proteins. Nonetheless, it is believed that the actual cellular mechanisms that lead to cell death are very similar, so that is it likely that a discovery in HD will be applicable to KD. This paper deals with such a discovery.
HD is the result of a mutation in the gene that codes for the protein Huntingtin. The function of this protein is unknown but the expansion of the CAG region of the gene leads, as it does in the AR of KD, the formation of a toxic form of the protein. As was described above with regard to the AR, the expanded CAG region of the gene causes the cell to put in too many glutamine molecules (an expanded poly Q region) into Huntingtin and this, like with the AR, leads to inadequate degradation and the formation of toxic waste products – exactly as described above for AR. The resulting undigested fragment leads to the formation of oligomers and inclusions, just like in KD.
This paper describes results that suggest a possible mechanism by which the aggregation of proteins that leads to the formation of oligomers and inclusions can be prevented, at least in cell models of HD. These results appear to confirm the belief that stopping the formation of protein aggregation will prevent cell death and stop the disease progression.
Why we care:
These results do not mean that there is a cure for HD and KD just around the corner. They do, however, indicate that progress is being made on how these diseases affect the functioning of the cell and that the researchers are heading in the right direction. It certainly appears that preventing the aggregation of poly Q proteins in the cell will prevent cell death and should stop the disease progression, the problem is how to do this in an intact (and living) person.
If you have any questions dealing with KD that you would like me to answer, or if there is a topic dealing with the science of KD that you would like me to write about, please send an email with your request to emeyerth@austincc.edu.