Tackling DNA damage and senescence pathways to identify new therapeutic targets for SBMA

Kennedy disease, also known as spinal and bulbar muscular atrophy (SBMA), is an untreatable and incurable disease affecting primarily voluntary movement, ambulation, and swallowing, and causing other peripheral symptoms. Kennedy disease is caused by the expansion of a small tract composed of repetitions of a building block proteins, i.e. glutamine (Q), in a factor, the androgen receptor (AR), which results in the production of an AR with several Q that is too long (more than 37Q). This mutation affects those neurons that control voluntary movement by stimulating the skeletal muscles. Both motor neurons and muscles degenerate progressively with age. This request of funding to Fondazione Telethon is based on an idea that emerged within the last years, by analyzing the phenotype of cells, flies, and mice that others and we generated. We found that mutant AR triggers damage of the DNA, the key molecule that stores our genetic information, thus inducing a premature aging of the cells. This aspect has not been previously explored in the field of Kennedy disease. Over the last years, we obtained strong evidence in support of our idea (please, see Piol et al., Sci. Adv. 2023). Now, we request funding to map the activation of these processes, elucidate how and why they are activated, and test the efficacy of drugs already in use for prostate cancer (also caused by mutant AR) for therapy development for Kennedy disease patients. If we succeed, then we will propose to bring these drugs forward for therapy development.