Protein Quality Control in Brain Aging: Lessons from Protein Misfolding Disorders in Drosophila

Abstract

Protein quality control is an essential process for cellular survival. When protein damage occurs, a series of coordinated response mechanisms repair or degrade damaged proteins to avoid the accumulation of toxic protein aggregates and restore proteostasis. However, the amount of misfolded proteins increases during aging overwhelming the mechanisms responsible for protein quality control, thus leading to the development of several age-dependent neurodegenerative disorders. Interestingly, targeted expression of proteins causative of these diseases in flies reproduces the pathological behaviors seen in humans. This remarkable conservation provides a valuable experimental tool to elucidate the complex mechanisms associated with the maintenance of proteostasis. In this chapter, we summarize how Drosophila has contributed to understand the roles of the heat shock response, the unfolded protein response, autophagy and the ubiquitin proteasome system in brain aging and neurodegeneration associated with proteinmisfolding disorders. In addition, we describe fundamental contributions of the fly system to the design of new therapeutic strategies for these devastating disorders.