Alternative translation initiation as a novel strategy to block toxicity of the mutant Androgen Receptor in SBMA

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s Disease (KD), is a rare inherited disease which affects adult male; the disease is associated to damages to the nerve cells which control movement and the muscle tissue. SBMA is due to a genetic defect of the androgen receptor (AR) which causes an elongation of an aminoacid sequence of glutamine, normally present in the AR. In SBMA patients, the length of this elongated polyglutamine stretch (polyQ) in the AR is twice (longer than 36 polyQ) that present in normal individuals (20-25 polyQ). The elongated polyQ confers toxicity to the mutant AR (ARpolyQ) and this toxicity is triggered by the AR ligand testosterone. This well explain why only male are affected, while female carrying the mutant AR are protected from the disease. These data have suggested to search for drugs capable to inhibit AR production and/or activation, but have the considerable side effects to impact on male endocrine functions. In our project, we proposed an innovative approach taking advantage of the peculiar structure of the messenger RNA coding for the AR protein. In fact, the AR is normally produced using an initiation sequence, called AUG, located upstream to the sequence which determines the insertion of the neurotoxic polyQ tract inside the AR. Notably, a second initiation UG sequence exists in the AR mRNA, and this is located right after the region which produce the PolyQ. The use of this second AUG give rise to a shorter AR protein which retain its function, but devoid of the neurotoxic polyQ tract. In our project we will utilize genetic and/or pharmacological approaches which may favor the production of the shorter AR form lacking the polyQ, thus not toxic. The identification of compounds capable to generate this AR form may results in the formulation of drugs which a great therapeutic potential in SBMA.