ROLE OF THE UNFOLDED PROTEIN RESPONSE IN THE PATHOGENESIS OF POLYGLUTAMINE DISEASES

Expansion of a polyglutamine tract is responsible for nine neuropathies, including Huntingtons disease and spinal and bulbar muscular atrophy. Polyglutamine diseases are late-onset genetically inherited neurodegenerative disorders, characterized by impaired neuronal function and death. To date, there is no therapy for the diseases. Since the expanded polyglutamine tract is a common feature, the pathomechanism is likely to be the same. However, selective brain areas are affected in the different disorders. Expanded polyglutamines form intracellular aggregates. Although the presence of aggregates has been correlated to the pathology, the mechanism of action of the mutant proteins is not known. Fragments of mutant proteins sequester cellular components involved in protein degradation, impairing their function. Inhibition of degradation results in the accumulation of aberrant proteins in various subcellular compartments and activation of the “unfolded protein response” (UPR), a signaling pathway devoted to increase protein folding or degradation. If cell homeostasis is compromised, the cell dies. The finding that expanded polyglutamines activate the UPR in cell leading to cell death suggests for this pathway a role in the disease. We will explore whether the UPR is induced in vivo in mouse models of the diseases, how it contributes to the pathogenesis and why diverse brain areas are affected. Since the UPR can be pharmacologically inhibited or activated, this pathway represents a good target to develop therapeutic treatments for patients. Therefore, a screening for therapeutic compounds (available at the National Institutes of Health, Bethesda, USA) active on the UPR will be carried out to develop effective therapies.