Motor neuron degeneration in Spinal and Bulbar Muscular Atrophy: molecular approaches to counteract mutant androgen receptor neurotoxicity

Spinal and Bulbar Muscular Atrophy (SBMA) is a neurological disorder affecting motoneurons, 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 disease, which has been linked to a mutation of the androgen receptor (AR) gene. Animals and motoneuronal 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 abnormally folded (misfolded) proteins, whose formation is triggered by testosterone. Not always misfolded protein aggregation parallels neurodegeneration, but are still indicative of alteration in the degradative systems responsible for their clearance. It has already hypothesize that a role in the pathology is played by dysfunctions of the intracellular degradative pathways, and this leads to increased intracellular concentration of the neurotoxic protein. In particular, the autophagic pathway seems to be affected by the mutant AR. In this study, we will investigate at which step(s) failure of protein degradation via autophagy occurs in motoneurons SBMA. We will also use molecular and pharmacological approaches specifically designed to improve the autophagic clearance of mutant AR. In addition, possible cell specific selective alterations induced by the mutant AR in motoneuron and muscle cells will be evaluated.