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.
A $25,000 grant was awarded to Maria Pennuto, Ph.D. from the National Institute of Health. Dr. Pennuto has spent the past few years investigating the molecular switches on the AR that are involved in the movement of the AR into the nucleus upon addition of hormone. She has discovered that certain chemical changes to the AR seem to reduce the ability of the AR to bind to hormone and thus not enter the nucleus (and cause KD!!). She has discovered that the exposure of cells to a substance known as IGF-1 can induce these chemical changes to occur to the mutant AR and thus prevent the movement of the AR to the nucleus. Thus, the addition of IGF-1 to a cell with mutant AR appears to prevent the formation of the toxic fragment and thus the cell stays alive. Dr. Pennuto will continue this work by determining if any other chemical changes to the AR may alter its movement to the nucleus and she will also determine if IGF-1 prevents the formation of KD symptoms in a KD mice model (up to this time, the effect of IGF-1 has only been shown to work in cell cultures. This work could lead to new therapies for KD.
