Aggregates deposition in neurons of patients is a generic feature of neurodegenerative diseases like Huntington's disease, Parkinson and Alzheimer's diseases. The mechanism of aggregates formation is unknown. The aim of this thesis is to study the mechanism of polyglutamine proteins aggregation. We have discovered that cellular environment plays a central role in the polyglutamine protein aggregation mechanism (Rousseau et al., 2004). This suggested that some factors modulate polyglutamine protein aggregation in cells. Looking for these factors, we found that two subunits of the 19S proteasome, Rpt6 and Rpt4 enhance the aggregation of the Huntingtin protein in cells. Down regulation of Rpt6 by siRNA decreases Huntingtin inclusion formation. When targeted to the proteasome by a ubiquitin independent pathway mutant Huntingtin is efficiently degraded. Aggregation of mutant Huntingtin protein is not a consequence of a proteasome proteolytic failure but is elicited when unfolding by the chaperone subunits of the 19S particle is uncoupled from proteolysis by the 20S proteasome. This work highlights the key role for cellular environment and particularly 19S proteasome in the control of polyglutamine protein aggregation.
