Connections between protein degradation pathways and trinucleotide repeat disorders

The discovery of expansion mutation in polyalanine tracts as the cause of a growing number of human diseases, has promoted efforts to understand the pathology involved. Currently, there are eight known disorders with polyalanine expansion mutation in different transcription factors. Most cases are sporadic and are caused by de novo in-frame duplications. Congenital neurological disorders are observed in many polyalanine disease patients, where the severity of the disease is often correlated with increasing length of the polyalanine tracts. Examples include mutant PHOX2B in congenital central hypoventilation syndrome (CCHS) and mutant SOX3 in X-linked mental retardation. So far, efforts have been focused to study each one of the diseases independently. Recently, we discovered connections between polyglutamine tracts and the degradative pathway of autophagy, thus suggesting a new model of shared biological mechanisms between different polyglutamine expansion diseases. This led us to explore for the first time the existence of common cellular mechanisms between polyalanine diseases. We have recently completed a proteomics screen and identified common targets interacting with isolated polyalanine tracts. Our hypothesis is that exploring the cellular functions of polyalanine tracts in normal proteins is important for understanding their role in disease. To test the physiological relevance of our findings, we are developing polyalanine disease models of CCHS. The identification of common targets across these diseases can stimulate basic and translational research, with the promise of treating not only one condition but the entire class of polyalanine diseases.