Protein Oxidation, Quality-Control Mechanisms and Parkinson’s Disease

Abstract

Proteostasis is defined as the integrated mechanisms within cells that control protein biogenesis, folding, trafficking and degradation. The integrity of the proteome is essential for cellular homeostasis, function and survival and is continuously challenged under both physiological and pathological conditions. Cells have evolved a complex and hierarchical array of processes called protein quality control mechanisms to ensure protein integrity that include chaperones and protein sorting/segregation and degradation pathways. Protein quality control starts even before protein synthesis and continues throughout their ‘lifespan’. Accumulation of misfolded protein aggregates is a hallmark in Parkinson’s disease (PD). The loss of dopaminergic neurons in the substantia nigra is linked to the presence of intraneuronal inclusions called Lewy bodies (LBs). Alterations in protein quality control mechanisms involved in protein folding and clearance of misfolded protein aggregates are linked to the pathogenesis of PD. In this chapter, we will review the proposed mechanisms by which PD risk factors (aging, genetics and environmental exposures) promote protein misfolding and aggregation and impair protein quality control mechanisms. Special emphasis will be placed in the role of oxidative stress in the dysfunction in the chaperone network, the ubiquitin-proteasome (UPS) and the autophagosome-lysosome system in PD.