MOTONEURON DEGENERATION IN SPINAL AND BULBAR MUSCULAR ATROPHY: FROM THE MOLECULAR MECHANISMS TO THE POTENTIAL THERAPEUTICAL APPROACHES

Spinal and Bulbar Muscular Atrophy (SBMA) is a neurological disorder affecting motor neurons, i.e. the neurons responsible for the contraction of muscles that control voluntary movements, speach, swallowing, respiration. The disease is characterized by a progressive paralysis that leads to death for respiratory failure. From a molecular point of view, SBMA is an inherited neurodegenerative diseases which has been linked to a mutation of the androgen receptor (AR) gene. Animals and motor neuronal cellular models of SBMA have been produced in recent years; these models have allowed to determine that the neurotoxicity of the mutant AR can be modulated by the AR endogenous activator testosterone, providing novel strategies to treat the diseases. By taking advantage of this peculiar aspect of SBMA it has been demonstrated that vulnerable neurons contain aggregates of abnormal proteins, whose formation is triggerd by testosterone and whose accumulation parallels neurodegeneration. It is therefore possible to hypothesize that a role in the pathology is played by dysfunctions of the proteolytic pathways, i.e. of the mechanisms that normally degrade intracellular protein. In this study, we will investigate whether motor neurons degeneration in SBMA is due to a failure of protein degradation by analyzing two different intracellular proteolytic systems: the proteasome and the autophagosome?lysosome. We will also consider other mechanims of disease, for example the alteration of the active transport in neuronal processes, as well as the involvement of the muscle in the disease. Finally, we will find ways to reduce the intracellular levels of the neurotoxic AR protein by studying the promoter region of the gene controlling AR expression.