Investigate mechanisms to prevent the accumulation of the toxic fragment in cells containing the mutant AR
Summary: Two grants just funded by the KDA both attempt to investigate mechanisms to prevent the accumulation of the toxic fragment in cells containing the mutant AR.
Briefly, KD is caused by a genetic mutation to the gene that codes for the Androgen Receptor (AR) protein. This protein mediates all the actions of the androgen hormones testosterone and dihydrotestosterone, DHT. In the cells of normal males, the AR is found in the cytoplasm of the cell. Upon the addition of an androgen hormone (either testosterone or DHT), the hormone binds to the AR and the hormone/AR complex travels to the nucleus of the cell where it initiates the masculine changes that are associated with the presence of androgens (beard growth, for example). If there is no androgen present, then the AR never enters the nucleus and there are no changes – this is essentially what occurs in females. Since women do not possess androgens, the AR does nothing in cells and there are no masculine effects. The AR in the nucleus is ultimately destroyed by a cell structure known as the proteasome. In individuals with KD, the cell is unable to completely destroy the AR that enters the nucleus - but it can destroy the AR that does not enter the nucleus and this inadequate digestion apparently results in the production of a fragment of the mutant AR that is toxic to the cells – thus the cells die and this leads to the formation of the symptoms of KD. This appears to explain why women carriers do not show major symptoms. Since the levels of androgens in women are low, the mutant AR does not enter the nucleus and the cell does not create the toxic fragment.
Another $ 25,000 grant was awarded to Udai Bhan Pandey, Ph.D. from the University of Pennsylvania. The proposal by Dr. Pandey and Dr. Paul Taylor continues the work that they did (in part thanks to a previous KDA grant!). They previously reported that KD symptoms in a fly model of KD could be reduced by activating another mechanism for destroying the KD in the nucleus, by passing the need for the proteasome. This alternate pathway, known as autophagy, apparently is capable of destroying the toxic fragment. They did this by making the fly over produce another protein known as HDAC6. By doing this, they were able to demonstrate that the overproduction of HDAC6 did not show cell death despite the presence of the mutant KD. They will now try to continue this work as they attempt to find other proteins that may affect this activity of HDAC6 to stimulate autophagy and thus help prevent the cell death associated with KD.
