Role of the nascent polypeptide-associated complex NAC in proteostasis during aging and disease conditions

Abstract

Many age-related neurodegenerative diseases such as Alzheimer's, Parkinson's and polyglutamine (PolyQ) diseases, including Huntington's disease, are associated with the aberrant accumulation of specific protein aggregates in affected nerve cells. The accumulation of these protein aggregates, which reflects an age-related failure of the cell's protein quality control system, is causally linked to the pathogenesis of such protein conformational disorders, also called proteinopathies. To maintain protein homeostasis (proteostasis), cells invest in a large network of factors that counteract the misfolding and aggregation of proteins. At the top of this proteostasis network are molecular chaperones that specifically bind and protect unstructured polypeptides from aggregation. Some of these chaperone systems act directly at the ribosome tunnel exit and support the folding, maturation and transport of newly synthesized polypeptide chains in a co-translational manner. Although it is known that ribosome-associated chaperones have a crucial impact on the overall cellular proteostasis, their potential direct effect on disease-related protein aggregation has not yet been investigated. This dissertation focuses on the molecular chaperone function of one of these ribosome-associated factors, the eukaryotic nascent polypeptide-associated complex (NAC), and its role in preventing the accumulation of pathogenic protein aggregates